Document kDevzp5Kjx47e4jBV9RMagVEO

JOSEPH E. KELLER JEROME H. HECKMAN CHARLES M. MEEHAN WILLIAM H. BOROHE3ANI, JR. ROBERT R. TIERNAN WAYNE V. BLACK DAVID L. HILL MARTIN W. BERCOVICI PETER M. NEMKOV JOSEPH E. RADLEY, JR. CAROLE C. HARRIS MICHAEL P. MORRONE LARRY S. SOLOMON JOHN B. DUBECK CHRISTINE A. MEAGHER SHIRLEY S. FUJIMOTO JOHN S. ELDRED LAW OFFICES Keller and Heckman USO I7tl STREET, N W. SCITE lOOO WASHINGTON, D. C. 30036 April 4, 1978 0 TELEPHONE 303 497-UOO CABLE ADDRESS "KELMAN" WRITER'S DIRECT DIAL NUMBER 202/457-1110 APR 7 JQ73 To: All Members of: SPI--VCM/PVC Mailing List (Letter No. 38) Plastic Bottle Institute Plastic Beverage Container Group AN Safety Group PET Safety Group Food, Drug and Cosmetic Packaging Materials Committee PVC Safety Group -3 Letter Highlights J. (1) FDA has made available an assessT_nt of the risk of liver cancer from aflatoxin contamination of corn and peanut products, Copies are enclosed because of its relevance to estimating the risk associated with other substances such srcumpuiiSnts of packaging materials. (2) The risk assessment techniques applied by FDA with regard to aflatoxin are far less conservative than the risk assessments that have been submitted to FDA for food packaging materials. (3) Data from Professor Maltoni's ingestion studies of acrylonitrile and vinyl chloride-have become available and are dis cussed^--'Copies of the "final acrylonitrile report land exerpta ofj&g^'inyi chloride Interim report~^r'-enclosed. ASI-PR 0002625 April 4, 1978 Page Two (4) "Back-of-the-envelope" type risk calculations indicate that the latest toxi cological data will confirm that maximum projected migration of acrylonitrile and vinyl chloride from food packaging materials are well below an "acceptable tolerance level," even if much more stringent criteria than those used in the aflatoxin document are employed. A conservative tolerance level of 16 ppb for products like acrylo nitrile copolymer beverage containers and 52-104 ppb for polyvinyl chloride food packaging are estimated. Ladies and Gentlemen: As reported in our letter of February 28, 1978, Sherwin Gardner, Deputy Commissioner of Food and Drugs, has informally requested that risk assessments be performed for plastics packaging using the approach being developed by the Food and Drug Administration (FDA) with regard to aflatoxin and lead contamination. Accordingly we are sure you will be interested in reading FDA's newly released "Assessment of Estimated Risk Resulting from Aflatoxins in Consumer Peanut Products and Other Food Commodities," dated January 19, 1978, a copy of which we are enclosing. Notice of the availability of this risk assessment appeared in the Federal Register on March 3, 1978. FDA's risk assess ment for lead migration has not been published yet. We have recently obtained and are enclosing copies of additional information regarding the acrylonitrile and vinyl chloride studies of Professor Maltoni, Director of the Institute of Oncology in Bologna, Italy. These new data are crucial because risk extrapolations can most effec tively be performed only when complete data are available. Aflatoxin Risk Assessment By comparison to other risk extrapolations that have been submitted to FDA for food packaging materials (PVC and AN copolymers), the FDA assessment of the cancer ASI-PR 0002626 April 4, 1978 Page Three risk posed by aflatoxin could be termed recklessly nonconservative. Indeed, it is hard to compare the PDA assess ment of the risk presented by aflatoxin to existing calcula tions of risk for acrylonitrile or vinyl chloride since FDA's methodology with regard to aflatoxin departs drastically from previously accepted norms with respect to both the mathematical model employed and in the handling of the data. FDA's risk assessment for aflatoxin concerns itself solely with aflatoxin contamination of corn and peanut products since, according to FDA, these are the only prod ucts where such contamination is generally at a detectable level. FDA justifies ignoring the levels of aflatoxin in other food products on the grounds that considering them would not significantly alter the conclusions of the report. We are at a loss to understand why the level of aflatoxin contamination in other foods known to contain aflatoxin is not assumed to be at a level just below the sensitivity of analytical detection methods, an assumption FDA routinely applies to other products. Another interesting aspect of the risk assessment for aflatoxin is FDA's method of estimating dietary con sumption. Although the 90th percentile of consumption is considered, nowhere in the document is there any reference to a gluttonous consumer of peanut or corn products who might make corn or peanuts the major portion or sole con stituent of his diet, as was insisted upon by the Government in dealing with carbonated beverages in the hearing on acrylonitrile copolymer beverage containers; nor is any discussion devoted to the risk to a child who eats only peanut hufcfceT~gffir~5elly sandwiches. From a statistical standpoint, it isp ofcourse, proper to ignore such transient or aberrant dietary practices since they have little signif icance when assessing the average risk to the entire popula tion over a full life span. It appears that the Commissioner now concurs with this position although he chose to decide otherwise when dealing with beverage containers. A very significant non-conservatism in FDA's risk assessment concerns the level of confidence associated with its Mantel-Bryan risk extrapolation. In all previous MantelBryan extrapolations on acrylonitrile and vinyl chloride, the toxicological data was conservatively handled (i,.e., given a "worst case" interpretation) in a manner that yielded ASI-PR 0002627 April 4, 1978 Page Pour a 99% confidence factor for the result. This 99% confidence factor is part of the modified Mantel-Bryan procedure and was adopted by PDA in its Sensitivity of Method Regulation on Carcinogenic Animal Drug Residues. We have not been able to verify independently the confidence limit used in FDA's aflatoxin risk extrapolation, but the discussion on page 11 and the accompanying Table V suggest to us that no such conservative treatment of the toxicological data was applied before performing the Mantel -Bryan extrapola tion. The above comments barely begin to cover the incon sistencies between FDA's risk assessment for aflatoxin and the ultraconservative, by comparison, risk assessments that have been submitted to FDA for residual monomers that unavoid ably contaminate plastics packaging materials. Candidly, our general impression is that FDA made unsupported assumptions and distorted the numerical presentations in the aflatoxin document to support the conclusion it wanted to reach. We considered preparing SPI comments on FDA's afla toxin risk assessment, but have concluded that such comments would be more appropriate on the risk assessment for lead migration which is being prepared by FDA and should be available shortly. Inasmuch as FDA provided only a brief period for comment with respect to aflatoxin, and suspecting that an equally brief time will be allowed vis-a-vis any lead document, it may not be possible for us to go through normal full-scale clearance procedures with respect to comments on the risk assessment for lead. Nonetheless, we shall proceed on the basis that comments on the lead assessment will be desirable and will endeavor to get draft comments to a cross-section of SPI members for clearance prior to filing. Risk Assessments for Plastics Monomers A major criticism of risk extrapolations for both acrylonitrile and vinyl chloride have concerned the fact that they were based on the results of incomplete feeding data in one case and on inhalation data in the other. Pro fessor Maltoni has now completed his ingestion studies of acrylonitrile and vinyl chloride. A final report on the ASI-PR 0002628 April 4, 1978 Page Five acrylonitrile study has been published and we are enclosing a copy for your information. Professor Maltoni concludes that at a level of 5mg/kg administered three times per week, acrylonitrile exhibited a "borderline" oncogenic effect. We are hopeful, but not optimistic, that a final report on vinyl chloride will be forthcoming shortly. In the meantime, through the very gracious cooper ation of one of our members, a monograph presenting (in French) the papers and the ensuing discussions delivered at a Colloquium held in Paris on March 2, 1976, has now become available. Professor Maltoni presented a compre-` hensive review of his work to that date on vinyl chloride carcinogenicity and a full copy of his paper has been provided to the Food and Drug Administration (FDA). Because of the length of the paper, we cannot distribute it to all of you receiving this letter but we are enclosing copies of pages 25 and 26 of the monograph which report the results of the gavage (stomach tube) feeding experiments to that date. The conclusions Professor Maltoni drew from the almost completed feeding test (page 26) can be translated roughly as follows: (1) At 50 and 16.65 mg/kg VCM produces angiosarcomas of the liver and nephroblastomas; these two "tumors are"the~most characteristic produced by the monomer. (2) At 3.3 mg/kg the two angiosarcomas which have been observed were not located in the liver. (One appeared in the lung, the other near the kidneys.) (3) There is a clear relationship between dose of monomer and tumor response with a sharp drop-off between 16.65 and 3.33 mg/kg. Professor Maltoni further stated that in his experiments the 3.33 mg/kg dosage appeared to have a "border line" carcinogenic effect. He then reported that in another experiment in which animals were treated with 1 mg/kg, 0.3 mg/kg and 0.03 mg/kg, no tumors had been observed after 57 weeks into the test. ASI-PR 0002629 April 4, 1978 Page Six In our last letter to the SPI-VCM/PVC Mailing List (Letter No. 37), we discussed the need for completed toxi cology studies to provide a sound basis for a risk assess ment. Using the FDA risk assessment for aflatoxin as a model, the results of completed long-term feeding studies for acrylonitrile and the most recent vinyl chloride data, we are now in a better position to calculate the risk asso ciated with residual monomers that contaminate food packaging on a basis comparable to that used by FDA. As crude examples (the following should be considered to be merely illustrative and not definitive since it is based on the still incomplete Maltoni data for vinyl chloride and rule-of-thumb calcula tions) of how a Mantel-Bryan risk evaluation might work, Dr. Dixler has estimated the dietary concentrations for vinyl chloride and acrylonitrile that assure a risk to humans of no more than one in one hundred million (10"). You may recall that FDA used a risk level of 10" in its Regulation on Carcinogenic Animal Drug Residues. Because of conservatisms in the procedure, however, FDA has stated that the risk presented by its sensitivity of method approach is no more than 10". Vinyl Chloride Assume that the final Maltoni data for vinyl chloride indeed demonstrates that 3.33 mg/kg administered between four and five days a week is a "no effect" level. Since the vinyl chloride was administered only four to five days a week, we shall assume that the daily dose was 4.5/7ths of 3.33 mg/kg or 2.14 mg/kg. Applying the usual MantelBryan "worst case" assumptions, it can be roughly estimated that, at a 99% confidence level, 2.14 mg/kg would "produce" 4.5 cancers in 100 (4.5%). The Mantel-Bryan "safe" dose at a risk of one in one hundred million is approximately 1/8300 of the dose that causes a 4.5% incidence of cancer. There fore, a dietary intake of 2.14 divided by 8300 or 0.00026 mg/kg could be deemed "safe" as a total dietary exposure. Depending upon the assumptions used to convert mg/kg of body weight in the rat to parts per million (ppm) in the total diet in man, 0.00026 mg/kg is equivalent ASI-PR 0002630 April 4, 1978 Page Seven to 5.2--10.4 parts per billion (ppb) as the safe total dietary exposure for man. Since one can very conservatively assume that PVC could not package more than 10% of the diet, an actual migration level of ten times the safe exposure level could be set as a "tolerance." This tolerance (not more than 52-104 ppb migrating to food) assures that the risk of cancer could not exceed one in one hundred million. In this light, it would certainly seem reasonable to us that a finding of "non-detectable" with an analytical method sensitive to 2 ppb should be deemed to assure virtually absolute safety. Acrylonitrile A similar exercise for acrylonitrile, assuming that 5 mg/kg administered thrice weekly is a "no effect" level, also gives an approxi mate safe total dietary exposure for rats of 0.00026 mg/kg. For a 60 kg (132 lb) person, this is equivalent to a daily intake of 0.0156 mg, as posing a risk no higher than one in one hundred million. Based on the 90th percentile for carbonated bev erage consumption (1 liter/day) and assuming all such consumption were from acrylonitrile copolymer packaging, the acceptable migra tion tolerance would be 16 ppb. If we make the more reasonable assumption that no more than 50% of the carbonated beverage con sumption were packaged in AN copolymer containers, a tolerance of 31 ppb would assure virtually absolute safety. Here again, the present analytical sensitivity of 10 ppb is sufficient to reduce any risk from AN to below any meaningful level. We are sure you will recognize that the foregoing exercises in arithmetic are provided merely to show how important completed toxicology studies are in order to provide a firm basis for risk assessments. In addition to animal studies, FDA would also consider such epidemio logical data as can be presented, as well as other methods than the Mantel-Bryan procedure for extrapolating from observed risks at high exposure levels to estimated risks at infinitesmal exposure levels, as was done for aflatoxin. ASI-PR 0002631 April 4, 1978 Page Eight The risk that society might accept for a food packag ing material may well be less than the risk considered acceptable for aflatoxin in food. Be that as it may, justice would seem to require that the relevant risk assessments be carried out in a consistent fashion or one is left trying to compare apples to oranges. Even with the biased comparison, the conservative risk assessments that have been done for acrylonitrile and vinyl chloride predict a risk orders of magnitude lower than that accepted by FDA for aflatoxin. It appears that if the acrylonitrile and vinyl chloride data were treated in a manner consistent with the FDA risk assessment for aflatoxin, the estimated risk associated ' with such food packaging would have to be deemed unworthy of any concern. There must be a finite level of risk that can be accepted for food packaging since it clearly has social utility. Even such staunch defenders of the public health as Senator Edward Kennedy (D.-Mass.), have now publicly recognized that absolute safety is unattainable. A copy of a speech given by Senator Kennedy at an FDA/EPA Symposium on risk-benefit which appeared in the Congressional Record is enclosed. It appears, therefore, that recent data concerning the toxicology of acrylonitrile and migration potential (or lack thereof) for vinyl chloride, as well as public and legislative opinion are beginning to realign in a way that may yet make it possible for FDA to acknowledge the existence of a slight risk with respect to packaging materials in general, and that the risk from assumed acrylonitrile or vinyl chloride (and ultimately for any other residual monomer that becomes a concern) migration is trivial and not worthy of regulatory attention. We shall, as usual, keep you up-to-date regarding the various regulatory activities relating to vinyl chloride polyvinyl chloride and acrylonitrile. In the meantime, those of you who require a complete copy of Professor Maltoni's paper are requested to contact us so we can make special arrangements with you to make it available. Cordially yours. Enclosures ASI-PR 0002632 "> - i r c ASSESSMENT OF ESTIMATED RISK RESULTING FROM AFLATOXINS IN CONSUMER PEANUT PRODUCTS ANTI OTHER FOOD COMMODITIES BUREAU OF FOODS FOOD ANT) DRUG ADMINISTER January 19, 1970 ASI-PR 0002633 r rSUMMARY AlChough direct proof that aflatoxins (3^, 32, G^, G2) induce cancer in humans does not exist, laboratory tests have demonstrated that they are animal carcinogens. Further, epidemiology studies in Thailand and parts of Africa show a significant relationship between liver cancer incidence and estimated levels of aflatoxin intake. Aflatoxins cannot be completely eliminated from food products without eliminating the products themselves. FDA has bean enforcing a limit of 20 parts per pillion (ppb) for aflatoxins in certain foods and is considering reducing that limit to 15 ppb for peanuts and peanut products (39 FR 42748). Unfortunately, the direct risks, if any, to humans from ingestion of aflatoxins cannot be measured. Therefore, risk assessments must rely on mathematical treatment of animal toxicology and epidemiology studies. Such risk assessments have been made by FDA and are described herein. Aflatoxins can occur in a variety of grains and nuts and can also occur in the meat, milk, and eggs of food animals that have consumed aflatoxln-containing feeds. Corn products and peanut products only have been considered in the risk calculations since inclusion of other products, because of contamination levels and/or frequency of contamination or consumption does not significantly affect the numerical results. Emphasis has been placed on com products in the Southeastern United States because both consumption and aflatoxin contamination levels are relatively high in that region. ASI~PR 0002634 rV 2- - Utilizing FDA and USDA aflacoxin survey and food consumption data, it is estimated that aflatoxin intake ranges from an average of 2.7 to a maximum of 9.0 nanograms/kilogram of body weight/day (0.1 to 0.3 parts per billion in the diet) in the Southeast. _ " An extensive body of data exists on aflatoxin toxicology in laboratory-animals. 3ecause it would be impractical to make risk calculations for each such study, five studies, involving long-term feeding of aflatoxins to three species of rats, were selected. (Fats in general, and male rats of the Fisher strain in particular, are considered the most aflatoxin-susceptible mammals.) Using the mathematical procedure of Mantel and 3ryan, estimates of lifetime liver cancer incidence rates were derived for each study, and for the five studies combined. These estimates range from 30 to 1400 per 100,000 for the individual rat studies and from 240 to 1100 per 100,000 for their combination. 3y way of comparison, risk estimates derived from studies on rats and ocher species combined by Cornfield and co-workers yield a range from 17 to 126 per 100,000. The actual lifetime liver cancer incidence rate from all causes in the U.S. is approximately 161 per 100,000. Actual incidence rates in Georgia and Alabama are approximately 103 and 100 per 100,000 respectively. (Rates for other Southeastern states are not readily available.) The fact that the risk estimates for rats in general exceed the human incidence rate for liver cancer from all causes can be attributed, in part, to the conservative mathematical procedures employed. In ASI-PR 0002635 r 3r addition, available in vitro data would indicate that humans are biologically closer to relatively resistant animals such as mice and monkeys than to aflatoxin-susceptible rats. Epidemiology studies conducted in Thailand and several parts of Africa show a positive correlation between actual liver cancer incidence and estimated intake of aflatoxins. Utilizing the relation ship derived by Peers and Linsell, risk estimates were calculated to range-from 20.2 co 67.0 per 100,000 for estimated average and maximum aflatoxin intakes. How applicable such epidemiological studies are to the U.S. is not known, particularly since the liver cancer incidence rates in these areas outside the U.S. may be greatly influenced by the presence of pyrrolizidine alkaloids in herbal medicines and the existence of hepatitis-3 virus. Risk estimates calculated from the epidemiology data for peanut products only yield a range of 1.1 to 2.7 per 100,000. Assuming chat a proportional reduction in aflatoxin levels would result from the ^ proposed regulatory enforcement limit of 15 ppb yields a projected range of 0.8 to 2.1 per 100,000. For the lowest enforcement limit currently possible, 5 ppb, the theoretical range would be 0.3 to 0.7 per 100,000. Although the ranges are broader, the animal data yield a similar comparison between a limit of 15 ppb and that of 5 ppb. Neither che estimated incidence races calculated from the animal data nor chose from the epidemiology studies can be construed as representing the actual human risk from aflatoxins. It is reassuring, ASI-PR 0002636 r 4r however, that the two approaches yield similar results, at least when inter-species differences are taken into account. Assuming that these approaches at least provide conservative indications of potential human risk, there appears to be little, if any, gain in public health protection associated with a tolerance for aflatoxins in peanut products at 10 ppb or S ppb as opposed to the 15 ppb level being considered. Again assuming that these approaches have some validity, it appears prudent to continue efforts to control the largelv intra-state problem with aflatoxins in com in the Southeast--notwith standing the apparently lower actual incidence of liver cancer in the Southeast. The several other reasons why a 15 ppb tolerance for aflatoxins in consumer peanut products is deemed appropriate were described in the I preamble to the proposal to establish the tolerance. ASI-PR 0002637 rc INTRODUCTION " ---------- -- -- The Food and Drug Administration * (FDA)'' is considering a regulation that establishes a tolerance for aflatoxins"in shelled'peanuts and peanut products used as human food. The'regulation"woula sec a 15 parts per billion Cpp'o)' tolerance for total aflatoxins'(B^`-t-'B^'+ 0^" + i:i -iiese product's. Aflatoxins are mold-produced toxins which are unavoidable contaminants in peanuts and a number of other food commodities (1). Although the human health effects of chronic exposure to aflatoxins are not known with cartaint; there is evidence which associates chronic dietary exposure to aflatoxins with the induction of primary liver cancer. In particular, several studies -have indicted aflatoxins as animal carcinogens (2). _At present, it is not possible, to, determine, a level of dietary exposure .to carcinogenic substances that would not lead to a finite risk of human cancer. Therefore, assurance of absolute safety for the consumer (i.e., no risk of cancer) is achievable only through complete elimination of carcino genic substances from the diet and from other sources. However, unlike chemicals intentionally added to food, unavoidable food contaminants cannot be prohibited from the diet, unless the rood susceptible to contamination is itself prohibited. This approach to the assurance of absolute safety for food unavoidably contaminated with aflatoxin would mean the complete elimination of chose food commodities chat have been shown to be susceptible to such contaminacic These food commodities include corn, peanuts, sorghum, rice, wheat, soybeans walnuts, almonds, pecans, pistachio nuts, Brazil nuts, figs, and the adible ASI-pr 0002638 c r-2- cissue (~eac, eggs, and milk) from food-producing animals that consume animal feed containing these compounds (3,1). 3ecause not all Iocs of these foods are expected to contain measurable aflacoxins, an alternative approach to indiscriminately eliminating from the diet both contaminated and non-contaminated food is to prevent from entering consumer channels only those lots demonstrated to contain aflatoxin. In the case of consumer peanut products, aflatoxins at or above a level of 5 parts per billion (ppb) can be measured with the degree of certainty required of FDA to initiate regulatory action (e.g., seizure) to prevent the marketing of aflatoxin-concaminated peanuts. In short, the goal of attaining a "zero" tolerance for aflatoxin would translate to an enforcement level of 5 ppb, i.e., the lowest level ac which it can be determined vitr; certaincy whether aflatoxin is or is not present in peanuts. (It should be noted that aflacoxins at levels less chan 5 ppb can be detected in peanuts, but the validity of measurements at such levels Is questionable.) While a level of 5 ppb may represent the lowest enforceable toler ance consistent with FDA's consumer protection objectives of minimizing dietary exposures to aflacoxins, such a tolerance would be beyond the capa bility of manufacturers to meet consistently. This is the case because of the high variability of aflatoxin levels within and among peanut Iocs. Such variability requires chat quality control limits in manufacturing be set much lower than the regulatory tolerance (5). For example, consistent production of lots conforming to the proposed tolerance of 15 ppb would require quality control limits on the order of 5-7 ppb. Lower tolerances would require pro portionately lower quality control limits. A tolerance of 5 ppb would thus ASI-PR 0002639 r r-3- require a quality control limit below the level of reliable detection and would result in the inadvertenc release of illegal lots into commercial channels, there to be seized by FDA. In brief, if peanut products are not to be entirely prohibited, consume exposure to aflatoxins from these products can only be kept below detectable levels (i.e. , 5 ppb) by seizure (and a significant loss of product). For a higher tolerance (e.g., 15 or 10 ppb), the emphasis would be on aanufacturir. quality control (and there would be less loss of product). 3ecause of the foregoing characteristics of the control situation, information is needed to assess the human risks associated with low levels of aflatoxin exposure. Unfortunately, such information is not readily avail able. However, evaluation of chat information which is available from toxi cology and epidemiology studies does help to put the risk question in per spective. In the following, risk estimates are derived from animal tests an. from epidemiology studies. Such estimates cannot be construed as represent!: actual human risk but they do provide an indication of the relative potanria toxicity of aflatoxins. INFORMATION NEEDED FOR RI3t< ASSESSMENT Existing data indicate that the most likely potential effect from chron: aflatoxin exposure i3 primary liver cancer (1,2), In all risk estimates to follow, it is this disease that is being considered. An estimate of the risk of primary liver cancer in humans due to exposu: to dietary aflatoxins requires two types of information. First, some measure of the toxicity of aflatoxin to humans must be available. For purposes cf ASI-PR 0002640 rr -4- this assessment, the most relevant toxicity data would be these relating long-term, low-level aflatoxin exposure to primary liver cancer in the exposet group. Ideally, what is sought is a dose-response curve expressing the relationship between the level of aflatoxin exposure (the dose) and the incidence of liver cancer (the response) in the exposed group. The most relevant and least suspect of such information would be that obtained by direct experimentation in human beings. Clearly no such data are available nor, for ethical reasons, could they ever be developed. Therefore, reliance must be placed on data resulting from: 1) epidemiological studies in groups of humans known to have been inadvertently exposed to aflatoxins; or 2) direct experimentation in laboratory animals. Epidemiological studies, which should provide the most relevant information obtainable, nonetheless ' have several disadvantages, perhaps the most important of which are their inherent limitations in establishing clear causal relationships and their relative insensitivity in detecting 3uch relationships. Studies in experi mental animals are usually more sensitive than epidemiological studies and, when properly conducted, are capable of establishing direct causation and dose-response relationships of relatively high certainty. But they have bean criticized on the grounds of being irrelevant to humans. It must also be kspin mind that epidemiological and animal data obtained from relatively small, homogenous population groups requires, for estimation of risks in an entire population, extrapolation to very large, heterogeneous groups of humans. It is not known how to estimate the uncertainty associated with extrapolations of these types. ASI-PR 0002641 r " r-J- In addition to toxicity information, risk assessment depends on data concerning the level and duration of human exposure to the toxic material. For purposes of this assessment, the relevant data are the food commodities in which aflatoxins occur, the levels of aflatoxins in those foods, the frequency and amounts of human consumption of those foods, and the length of time of exposure. As with the toxicity information, the human exposure factor in the risk assessment equation is also subject to much uncertainty. , M; DIETARY EXPOSURE TO AFLATOXINS a. Occurrence of Aflatoxins in Food: The food classes that contribute most significantly to dietary exposure to aflatoxins in the United States are dry milled corn products (e.g.^com meal and grits) and peanuts and peanut products (3). Exposure to aflatoxins through contaminated com occurs mainly in the southeastern states (i.ev North Carolina, South Carolina, Georgia, Alabama, Florida, Mississippi, and Louisiana), where the contamination of corn is most severe. In this area com is a dietary staple and the com consumed is primarily of local origin. On the basis of FDA and USDA survey data, it is estimated that the average level of total aflatoxins in dry milled com pro ducts has been in the range of 5-10 ppb (3,5,7). Com produced and consumed in other regions of the nation has a substantially lower aflacoxin content. Therefore, the United States population groups that appear to be at highest risk, those of the southeastern states, have been selected for emphasis in this risk assessment. To be conservative, the upper level of 10 ppb is used in the risk calculations. Peanuts, while grown in the Southern states, are processed and consumed throughout the councrv. Data from surveys conducted by FDA indicate an esti mated average level of 2 ppb cocal aflatoxins in consumer peanut products (3,6,7). This estimated level is equally applicable to population groups on a national or regional basis. ASI~Pr 0002642 r-6- As previously mentioned,-'-aflatoxins may also occur in ocher food com modities consumed in the United States'? -However, survey and experimental data indicate chat either the levels and/or-incidence of aflacoxin in these foods arid/dr-their ^onsump-btbn patterns'-a're'not'comparable to-chose found in peanuts and corn (3,6,7)." Calculations used rin-the estimates of total risx would not-be significantly-affected by ignoring these ocher food'items. The relevant data on the aflatoxin occurrence in food is presented in Table_I. TABLE I: Major Food Classes With Aflatoxins (3^ * 3^ + + G^) Food Class .. Peanuts and Peanut Products . Estimated Average Level (total aflatoxins, ppb) .. 2 Corn Products 5-10 * * Average is for Southeastern States; average in ail other areas is lower (see text). b. Consumption of Aflatoxin - Containing Food Products: A survey conducted by che u.S. Department of Agriculture (L'SDA) in 1965 provides the best available data for estimating human consumption of the significant food sources of aflatoxins (8). The USDA survey data were collected through personal interviews which required che respondent to recall all foods and che amounts actually consumed during the 24-hour period prior to the intervi The data collected, which covered the entire united States, are available.fo four major regions--Northeast, North Central, West, and South. ASI-PR 0002643 rr -7- For purposes of this risk, assessment, the data collected for che Southern region were used. This survey region included the states of Alab Florida, Georgia, Louisiana, Mississippi, N'orth Carolina, South Carolina, Arkansas, Kentucky, Delaware, District of Columbia, Maryland, Oklahoma, Te Virginia, and West Virginia. Although it would have been more appropriate base estimates of intake on the southeastern states alone (i.e., the first seven states listed), since dry milled corn products which may contain ail toxins are mainly produced and consumed in these states, the food intake estimates used in the risk calculations assume that dietary patterns of th South and Southeast are identical. Food intake estimates were used for the consumer peanut products and dry milled corn products listed in Table XI. TABLE II: Food Items From USDA Survey Used To Estimate Intake Of Aflatoxin-Susceptible Food (3). Consumer Peanut Products peanuts, shelled and in-shell peanut butter peanut butter sandwich peanut buttar S jelly sandwic peanut butter S banana sar.dwi peanut butter & jelly Dir/ Milled Corn Products corn bread & muffins corn pone spoonbread johnnycake hush puppies cornmeal pancakes corn grits, hominy grits cornmeal, cornmeal mush grits with fat fried cornmeal mush ASI-PR 0002644 r r3- - The estimated average levels of aflatoxins in consumer peanut products and dry milled corn products (Table I) are derived from surveys of these food items as marketed as opposed to food items prepared for consumption (i.e. , as eaten). Therefore, conversion factors were applied, where appropriate, to Che amount of intake of food items lisced in Table II to obtain the amount of intake expressed in terms of the food items listed in Table I. Calculation of the average and maximum daily intakes of foods susceptible to aflatoxin contamination also requires knowledge of the frequency at which these foods are consumed. Direct knowledge of the frequency of consumption of these foods is not available. To estimate daily consumption, it was necessary to make use of the information that the total population in the South surveyed by USDA consisted of 6,268 persons, 560 of whom had eaten peanut products and 1,530 of whom had eaten corn products during the 24-hour period preceding the questioning. Since it would be expected that these individuals would not consume these foods every day, the ratio of "eaters" for one day versus "non-eaters" for one day was used to establish the esti mated frequency at which these foods were eaten. This ratio, or frequency factor, was applied to both the average amount and to the amount consumed by the 90th percentile of the "eaters" surveyed to derive an estimate of average and maximum daily intakes. These estimates are presented in Table III. TA3L5 III: Estimated Consumption Rates For The Southeastern United States Of Food Products Which May Contain Aflatoxins. One day average - intake (grans) Peanut Products ^5 Com Products 53 One day maximum (90th percentile) intake (grams) 116 186 Factor for frequency of consumption .090 .252 Estimated average daily intake (grams) 4 14 Estimated maximum daily intake (grams) 10 47 ASI-PR 0002645 r c-9- c. Human Exposure eo Aflatoxins: The estimates of consumption contained in Table III can be combined with the Ievel3 of aflatoxin contamina tion (Table I) to estimate average and maximum human exposure to aflatoxins in the southeastern part of the country (the exposure in all other regions being lower). The results of these calculations are presented in Table IV. Also shown are the estimated average and maximum human intakes of dietary aflatoxin expressed in ng/kg body weight/day and in parts per billion (ppb) in the diet. TABLE IV: Estimated Average and Maximum Daily Aflatoxin Intake In The Southeastern U.S. DAILY AFLATOXIN INTAKE FOOD CLASS ng--1/ Average ng//k, g--2/ 22*T Peanut3 and 3 0.15 0.005 Peanut Products 1/ as- Maximum ng/kg 2/ . 3/ PPQ 20 0.37 0.013 Com Products 140 2.53 0.093 470 8.66 0.313 TOTAL 143 2.73 0.098 490 9.03 0.326 1/ ng * nanograms (1 x 10 grams) 2/ ng/kg body weight; average body weight of 34.3 kg 3/ ppb in diet; average daily food intake of 1300 g ASI-PR 0002646 c -10- RISK'ASSESSMENT a. Animal ToxicitV Data: The toxic effects'of aflatoxin have been examined in' Several studies in a'variety of species and strains of experi mental animals. These inciude'saveral~strains of~rats'is well as mica, marmoSets, etas shrews, trout; ducks, rhesus' monkeys', 1 and' hamsters (1). The literature Is much too extensive'to cover exhaustively in this report. Therefore, selected studies are employed in the following to illustrate the range of results obtained in animal studies. Generally, the rat, and in particular the male Fisher strain rat, is considered the mammalian species that is most sensitive to aflatoxin carcinogenesis (2). For this assessment, five studies involving three strains of rats were examined and the statisti cal procedure developed by Mantel and 3ryan (9) as modified (10) was applied to the experimental results*---This statistical proee4w?e-is one of several available which allow the estimation of carcinogenic risks associated with dose levels of the carcinogen below those necessary to yield a positive carcinogenic response in the animal experimentation. In the present example, the levels of interest are the average and maximum intakes, 0.1 and 0.3 ppb aflatoxins, respectively (see Table IV), Mo experiments have been conducted in rats at these low dose levels, so no direct measure of risk can be made; but, as noted, the Mantel-3ryan procedure can be applied to the available animal data to estimate the risks associated with the 0.1 and 0.3 ppb dose levels. It must be kept in mind chat the Mantel-3ryan procedure estimates animal, not human, risks. The relative sensitivities of humans and, in the present case, rats, remains to be considered. The results of che risk assess ment in rats are presented in Table V. ASI-PR 0002647 r -u' r As can be seen from Table V, the estimated lifetime liver cancer incidence-rates vary widely among the rat studies, ranging from a low of 30 to a high_.di.-_l.4QIl per 1001900.- Another indication of-ehe inherent variability in these-'experiments is'provided'By-the upper'99" confidence limits or"-risk shown* in-parentheses-in Table V. --- TABLE V: Estimated Lifetime Cancer Risks In Laboratory Animals (Rats)-- Incidence Rate Per 100,000^ DATA SOURCE (Reference No.) AFLATOXIX INTAKE (0.1 odd) (0.3 DDb) uiyr~ (12)' (13) (14) (15) ' ' 2/'( 60)-7 30( '220)" 70( 600) 140( 620) 320(1400) COMBINED RAI STUDIES COMBINED ANIMAL STUDIES^ 240( 470) 17( -- ) *2_/( 320)~ '*160( 990) 360(2300) 650(2400) 1400(4600) 1100(1900) 126( -- ) 1/ Incidence rates are based on the procedure of Mantel and Bryan (9), as modified by Mantel, e al. (10). 2/ Cannot be estimated. 3V Numbers in parentheses are upper 992 confidence limits. 4/ Includes rats, rainbow trout, ducks, and tree shrews. See text. Risks are graphically estimated. ASI-PR 0002648 -12- C The upper 99% confidence limits on the lifetime risks derived from the studies in Table V are not only conservative risk estimates (i.e., tr.ey represent a "worst case" estimace), but also are useful for comparing the several studies since the confidence limits t*ke into account differences in sample size and other variables in experimental design. Although the results of 'these five rat studies are too variable1 to justify statistically their pooling, they have been combined in Table 7 to indicate an overall level of response in rat studies involving different strains. Another approach to aflatoxin risk assessment based on animal studies is that taken by Cornfield, et al_. (16). Combining data from experiments on the rainbow trout, duck, tree shrew, and six different studies on five different strains of rats, these authors fitted various mathematical models. A probit model with a slope of 1.2 probits per log^g dose appeared to give the best fit. Estimates from graphs in this paper yield lifetime incidence rates of approximately 17 and 126 per 100,000 for doses of 0.1 and 0.3 ppb, respectively. As shown in Table IV, the average and maximum dietary intakes of afiatoxin contributed by peanuts are approximately 0.005 and 0.01 ppb, respec tively. For the combined rat studies, the risk estimates for these aflatoxin levels are 2 and 7 per 100,000, respectively. Utilizing the Cornfield approach yields risk estimates on the order of less than 0.1 per 100,000 (graphically estimated) for the 0.005 and 0.01 ppb levels. ASI-PR 0002649 r r-13- To assess the reasonableness of these animal derived risk estimates, it is of interest to compare them co the overall human liver cancer incidence rates in the United StatesThe `total crude-"i'ncTdence" `per year of primary liver cancer in "the total Unite"d'"S cafes'"p'o'p'uTac'io'ny "estimated" in'19'69, was '2.2/10^ (17). cor 'purposes' ~o f compaYison with* the" Tire time animal risk data, it 'is necessary to break down the'above crude yearly incidence rate 'in'terms of age-spe'cific rates, 'to multiply each age-specific race by a factor which reflects' the proportion of 'the "cofaT`liver cancer rate con tributed "by members oi'thac ag'e""group, "and'fheri 'to multiply each such agespecific "fate by'the expected'human lifespan o"f"70 years. Recombining the 'age"-specific rates yields' a calculated lifetime risk for liver cancer occurrence''of fol for`every'lCJO,000 in the total' 'U.'S. "population. Primary Tiver'"cancer lifetime 'incidence "races in Alabama and "Georgia, estimated in the same'"way, are 100/10^ and 103/10'', respectively (18). The rates for these two states, which are the on'l'y ones readily available for the souch"eas'cerri states,'are most appropriate 'for' 'comparison with the risks estimated from the'animal da'ca 'since they "represent'"the' "fe'giori 'with the highest antici pated exposure co aflatoxins. The risks calculated from the rat data in Table V not only differ greatly among themselves, demonstrating an intraspecies difference in sus ceptibility, but, at the 0.3 ppb dose level, individually exceed the lifetime risks of primary liver cancer in the human population of the United States from all causes. Possible explanations for these differences are: 1) the level of human exposure to aflacoxin has been over-estimated; 2) the Mar.talBryan extrapolation procedure is overly conservative in this case; and/or 3) rats may not be an appropriate model for predicting aflacoxin-iniucsd ASI-PR 0002650 r r-] 4- priaary liver cancer in humans. While data to rest che validity of che first or second explanation are not available, the third receives some cor roboration from studies showing differences in aflatoxin metabolism among various animal species, most relevant of which are the differences between rats and humans observed _in vitro. Available in_ vitro data indicate that the ability of an animal species to metabolize aflatoxin 3^ to a metabolite called aflatoxicol (AFL) is related to the sensitivity of the species to acute aflatoxicosis, and chat the ratio of reductive and oxidative activi ties, measured as the ratio of AFL concentration to chat of an oxidized metabolite known as Q^, is an index of species susceptibility to the carcino genic effects of B^. Although in vitro data for humans are extremely limited, the data available indicate that, with respect to these modes of metabolic behavior, humans are closer to relatively resistant species such as mica and monkeys than they are to che highly susceptible rat strains (19). b. Epidemiology Lata: Data reflecting actual consumption of aflacaxi.ns over defined periods of time by particular individuals who develop liver cancer are not available. The data most closely representing chat situation are those derived from studies in Thailand (20), Kenya (21), Mozambique (22), and Swaziland (23). For two or more districts in each of these councries, average aflatoxin concent in samples of meals actually consumed were deter mined. These estimates of average aflatoxin content were then correlated with official annual liver cancer mortality statistics. As previously stated, there are limitations to these epidemiology data, not che least of which is their inherent inability to establish direct cause-effect relation ships. For example, any comparison based on these epidemiological data ASI-pp 0002651 r -15- rests on the assumption that sample meals are representative, that current contamination levels are indicative of past experience (i.e., 10-20 years ago), and that there is no significant exposure to other possible causes of liver cancer. With respect to other possible causes, there is evidence that pyrroli- zidine alkaloids consumed in herbal medicines and hepatitis-3 virus may play a role in the etiology of primary liver cancer in some of the areas studies (24,25). Thus, the appropriateness of applying the human epidemiology data derived from these studies to low-incidence western countries is question able. Several other interfering factors, well-described by van Rensburg (24), further cloud the epidemiological data. The calculations made below should be considered against this background of uncertainty. The results of the various epidemiology studies have been standardized by van Rensburg (24) and these data are presented in Table VI. There is a highly significant positive correlation between cancer rate and estimated level of aflatoxin intake in the geographical areas studied, and a linear relationship between log aflatoxin 3^ level and cancer incidence, expressed as follows: y - 6.449 log x - 2.4115 where y * total cancer rate/10.5 /year and x - aflatoxin concentration in ng/kg/body weight/day. 4$I~pR 026S2 r C-16- TABLE VI:" Summa'rlzad Results of Ebidesiology Studies Measuring Primary "`Liver Caticer'Rate'and A'flatokin'Intake-(ng/kg body veight/day). ' ' ' (From Reference 24t}------ -- - ---- t _ c:: Locality-. ; r` - r'.......... = ; - -ilW"- - - - - -- i: Cancer-Rate-(10^/year) "- Kenya - High Altitude Thailand - Songkhla Swaziland - Highveld Kenya - Middle Altitude Swaziland - Mlddleveld Kenya - Low Altitude Thailand - Ratburi Swaziland - Lowveld Mozambique - Inhambane ................... 0.7 2.0 2*2 2.9 4.0 4.2 6.0 9.7 13.0 -- Estimated Aflacoxin Intake Cng/k3 body weight/day x - l': \; 3.5 5.0 <fi( 5.1 , J* 5.8 .OlO 8.9 , Sl'X- 10.0 . - 45.0 /L-y } 43.1 222.4 1 ASI-PR 0002653 r r-17- Using the estimated average and maximum chronic exposures for dietary levels of aflatoxins in che southeastern states (2.7 and 9.0 ng/kg body weight/day,respectively, Table IV) and che lo'g relation between dietary aflatoxin and cancer incidence derived from the epidemiological studies, the calculated range in the expected crude cancer incidence/year is 0.37 to 3.74 per 100,000. The actual crude ratas/10J/year in Alabama and Georgia are 0.97 and 1.18, respectively (18). It should be noted that the above calculations involve a significant assumption thac quite possibly is not the case. They assume that the back ground liver cancer rate (i.e., that rata due to unknown factor(s) other than aflatoxin present in the areas of the epidemiological studies) is equal to that of the United States. Of course, there is also the implicit assump tion thac aflacoxin contributes to the rata of liver cancer in this country; there is no evidence chat this is true. And certainly there are other sub stances in the environment, including the workplace, that are known to be hepatotoxic and could contribute to this disease rate. In an attempt to reduce che effects of this possible error, a different type of risk estimace has been made. Specifically, a linear, non-logarithmic relationship, derived from the human epidemiological data tabulated by Peers and Linsell (26), allows estimation of the human cancer rate related to dietary aflatoxins (or to other interfering factors, since these epidem iologic studies cannot conclusively show chat the increased race of liver cancer above background is due only to dietary aflatoxin). The relationship is: y * .106 x + 2.2, where y and x have the same meaning as above and 2.2 is the background cancer incidence/lO^/year when x * 0. ASI-PR 0002654 r .... r . . . -13- - - - :- . - ESTIMATES OF RISKS AX ALTERNATIVE TOLSmCEff. ^ ...Using Che lasc derived relationship, theoretical - risk estimates have made for various aflatoxin levels chat might result,from alternative toler ances*. Theseare shown in^Table VII ;and are based.on the assumption that the legal maximum level of aflatoxins in peanut products is directly pro portional to the average level of aflatoxins actually found in these products. For.example, the current FDA action level of 20 ppb leads to survey estimates of average levels of. 2 ppb in peanuts .and peanuts products and 10 ppb in dry .milled com products. -This -information. is -based .on..data collected while the 20 ppb action level was in affect for all food commodities. If one assumes a direct proportional relationship, -a reduction of the 20 ppb level to 15 ppb .for peanuts .and peanut products could produce, an average level of 1.5 ppb aflatoxins .in this-type-of food* . Similarly, a reduction of the tolerance .ta XQ .ppb and .5 ppb -could produce average 1-e.vels w ,1.0 ppb and 0.5 ppb, respectively. Since, for purposes of this assessment, the legal limit for .com is not under consideration, the estimated average level of aflatoxins .in this food is held constant. _ ............ . ___ _____ ASI-PR 0002655 tarlf, vf i : estimated Lifetime Cancer Hates Rased on Epidemiology Studies - Incidence Rates Per 100,000 --1 A T ? atnx in Love] (Pl'b) O 2 1.5 1.0 0.5 2/ PRANOTS Risks Resulting From _____ Daily Intake^ Average Maxi mum 1.1 0.8 0.5 0.3 2. 7 2.1 1.3 0. 7 CORN 3/ Aflat ox In Risks Resulting From /,/ Level_______________ Daily Intake--______ (ppb) Average Maximum j-oiAr Risks Resulting Front Daily Intake- Average Max Innim 10 19.1 64.3 10 19.1 64. 3 10 19.1 64.3 10 19.1 64.3 20.2 19.9 19.6 19.4 67.0 66.4 65.6 65.0 \J Rased on Peers and Llnsell (2fi) . Sec text. 2/ ^Ulatoxln levels are those which might be expected in peanuts and peanut products IF the tolerance were reduced from the current 20 ppb to 15, 10, and 5 pph, respert Ively. 3/ Aflatoxln levels in corn products assumed to he an average oF 10 ppb. A/ Incidence rate per 100,000 population. t # 'i .4 j C (-20- As shown in Table VII, the theoretical cancer rates over a lifetime cf exposure (70 years) are estimated for the Southeast to range from 20.2 to 67.0/10^ at the current 20 ppb action level; 19.9 to 66.4/10^ at a 15 ppb tolerance, 19.6 to 65.6/10 at a 10 ppb tolerance and 19.4 to 65.0/10 at a 5 pob tolerance. Thus, based on the epidemiological data (26), assessment of the estimat risk of human exposure to varying levels of aflatoxins in peanuts -and peanut products shows relatively no significant gain in the protection of the publi health (i.e., reduction in liver cancer) by adopting a tolerance of 5 ppb (currently the lowest enforceable tolerance) as opposed to FDA's proposed tolerance of 15 ppb. This analysis applies to the population at highest risk, namely that of the southeastern United States. In ocher areas of the country, where aflacoxin contamination of corn is not a significant problem, the health risks from aflatoxins are due, for the most part, to exposure to contaminated peanuts. The estimated lifetime risk to humans from this source of exposure only, based on the same type of cal culations used to derive Table VII, ranges from 0.8 to 2.0/10, if it is assumed chat all peanut products contain 1.5 ppb aflatoxins (under the pro posed 15 ppb tolerance). This theoretical lifetime risk of cancer would be reduced to 0.5-1.3/10^ at a 10 ppb tolerance and 0.3-0.7/10 at a 5 ppb tolerance. For the convenience of the reader, the lifetime liver cancer incidence rates listed in the foregoing cables are summarized in Table VIII. ASI-PR 0002657 r .21. r TABLE VIII: Suninary of Maximum Expected Lifetime Liver Cancer Incidence '"Rates Due to Aflatoxin Exposures Under Current FDA Guideline of.20 P?B. . _ . . ,-. Actual Incidence Ratas^ Total U. S. - 161 per 100,000 Alabama. 7 100 per. 100,000 Georgia - 103 per ICO,000 L Estimated Incidence Rates Due to Aflatoxins . . 2/............ From Combined Rat Studies -- J......... . - Total Consumption: .Peanut; ,Products:0nly: 240'to'ilQQ per 100,000 2 to 7-_aer 100,000 From Combined Animal Studies -- Total Consumption: 17 to 126 "per 100,000 Peanut-Products Only Less chan .1 per 100,000 From Epidemiology Studies 37 Total Consumption: . ; --Peanut Products Only > - -' 20:2 to 67.0 per 100,000 1.1_Co_2;7-per 100,000.. 1/ See Text, pages 15, 2/ See Text, Table V. v See Text, Table VII. ASI-PR 0002658 (1) Rodricks, J. V., Hesselcine, C. W. , and Mehlman (Ids), Mvcocoxins in Human and Animal Health, Pathotox Publishers, Park Forest South, 111 o is , 1977; pp. 6-136. f2) Wogan, G. N. (1973) Aflacoxin Carcinogenesis, in Methods in Cancer Research, Vol. VII; H. 3usc'n (Ed.), Academic Press, Hew York, Haw York, pp. 309-344. (3) Stoloff, L., Aflatoxins--An Overview, in Reference 1, pp. 7-23. (4) Rodricks, J. V., and Stoloff, L., Aflatoxin Residues From Contaminated Feed in Edible Tissues of Food-Producing Animals, in Reference l,'*pp. 57-7 (5) Tiamstra, ?. J., Aflatoxin Control Curing Food Processing of Peanuts, in Reference I, pp- 121-138. (6) Lillehoj, G. 3., and Hesseltine, C. W. , Aflacoxin Control During Plant Growth and Harvest of Corn, in Reference 1, pp. 107-119. (7) Stoloff, L., Occurrence of Mvcocoxins in Food and Feed, in Mvcocoxins and Other Fungal Related Food Problems, J. V. Rodricks (Ed.), Advances in Chemistry Series, Ho. 149, Am. Chem, Soc., Washington, D.C., pp. 23-50. (8) U.S. Department of Agriculture Survey of Household Food Consumption in the United States, 1965-1966; Food Intake of Individuals, Spring 1965 (com puter tapes). (9) Mantel, M., and Bryan, W. R., "Safety" Testing of Carcinogenic Agents, J. ^atl. Cancer Inst.. 27, 455-470 (1961). (10) Mantel, N., et al., An Improved Mancal-3ryan Procedure for "Safety" Testing of Carcinogens, Cancer Research, 35. 365-372 (1975). (11) Alfin-Scater, R. 3., e_t al., Studies of Long-Term Administration of Afla toxin to Rats as a Natural Food Contaminant, J. Arner. Oil Cham. Soc., 46, 493-497 (1969). (12) Newberne, P., and Butler, W. H. , Acute and Chronic Effects of Aflacoxin on the Liver of Domestic and Laboratory Animals, Cancer Res, 29, 236-250 (1969). (13) Wogan, G. H., ec_ _ai. , Carcinogenic Effects of Low Dietary Levels of Afla coxin 3j_ in Rats, Food Cosmet. Toxicol. , 12, 631-635 (1974). (14) Barnes, J. M., and Butler, Carcinogenic Activity of Aflacoxin to Rats, Nature. 202, 1016 (1964). ASI-PR 0002659 \t ri ( (15) Nawbeme, P., and %'illiaras, G. , Inhibition of Af-lacoxin Carcin05er.esis byHJiechylstilbestrol in Mala Rats, Arch. Environ. Health, 19, 459-493 (1969) (16) .COrCnflald, J. , at al. , Private Communication, 1977- (17) Biometry 3ranch, National Cancer Institute, Preliminary Report, Third National Cancer Survey, .1969 Incidence. National Institutes of Health, DHEW, 1971. (18) Stoloff, L., and Friedman, L., Information 3earing on the Evaluation of the Hazard to Man From Aflatoxin Ingestion, PAG 3ulletin, Vol. VI, No. pa, ;21-32.(1976), .... (19) Hsieh, D., e_t al. , Comparative Metabolism of Aflatoxin, in Reference 1, PP_._ ,37-50. - (20) Shank, R., al., Dietary Aflatoxins and Human Liver Cancer IV, Food Cosmet. Toxicol., 10, 171-179 (1972). (21) (22) "Peers, FT,** and' Linsell, C., Dietary Aflacoxins and Liver Cancer--A Poou lation Based Study in Kenya, 3rit J.. Cancer, 27, 473-434 (1973). t van Rensburg, S. J., et ai., Primary Liver Cancer and Aflatoxin in a High Cancer Area, S_. Afr. Med. J., 48, 2508a-2508d (1974). (23) Peers, F., et al., Dietary Aflacoxins and Human Liver Cancer, A Study in Swaziland, Inst. J_. Cancer. 17, 167-176 (1976) (24) van Rensburg, S. J., Role of Epidemiology in Elucidation of Mycotoxin Health Risks, in Reference 1, po., 699-712. (_2_5) Fakunie,. Y. M., et al. , Primary Liver Call Carcinoma (PLCC) -in-the Note Guinea Savanna of Nigeria, Trans Roval Soc. Troo Med. Hvg., _71, 335-337 (1977). (26) Peers, F., and Linsell, C. A., Dietary Aflacoxins and Human Primary Liv Cancer, Presented at III IUPAC Symposium on Mycotoxins in Foodstuffs, Paris, Sept. 1976. PR 0002660 AS I" r XnsQtute of Oncology and Tumour Caatre, Bologna, Italy c C. MALTONI ' A. CILIBERTI V. DI MAIO CARCINOGENICITY BIOASSAYS ON RATS OF ACRYLONITRILE ADMINISTERED BY INHALATION AND BY INGESTION Estratto d& * La Medicine del Lavoro * Vol. 68 - N. 6 - 1977 TIPOLITO MATTTOU * FDENZA ASI"PR 0002661 c"V c Institute of Oncology and Tumour Centre, Bologna, Italy CARCINOGENICITY BIOASSAYS ON RATS OF ACRYLONITRILE E.V ADMINISTERED "BY ` INHALATION AND'BY INGESTION E' '','7-1 ..E ON ANT' EA ... C. MALTONI A. CILIBERTI V. DI MAIO 1) Introduction Acrylonitrile (AN), or Vinyl Cyanide, G"-Ii = CHCN, has the following physical and chemical properties. Physical state: clear, colorless, volatile,-liquid, Molecular weight: 53.06, SiH-vific gravitv: OKOtM (25/4* C.l, lreeaiitg point: --i>3" C., Boiling point: 77.3* C., Refractive ir.dex: 1.3SS5 (25* C.), Vapor density: 1.9 (air as 1), Vapor pressure: 110-115 rr.tn. Hg (25* C.), Per cent in "saturated air": 14.5 (25* C.), Density of "saturated air*: 1.13 (25* C.) (air = 1). Solubility*: mixible with most common organic solvents, including acetone, benzene, carbon tetrachloride, ether, ethyl acetate, ethylene cyanohydrin, me thanol, petroleum ether, toluene, xylene and some kerosenes. AN is a very versatile and industrially important chemical intermediate. Its reactions may involve the evano (CN) group alone, the activated double bond (C=C>. or both groups. The most important reaction, commercially is its polymerization: in fact it is used mainly (95^ of the total use) as a monomer or a comonomer (with styrene and butadiene) for the production of synthetic textile fibers, plastics and rubber elastomers. AN gives important properties to polymeric materials: SASI-pr 0026 2 402* r MALTONt, CILIBE&TI, DI MAtO c M,U.LtiO~a ability to form oriented fibers; and impact, thermal, chemical, solvent and weather resistance. It also undergoes many reactions to form compounds used as solvents, plasticizers, and dyes, pharmaceutical and insecticide intermediates. AN has, moreover, other different uses. For example, cyanoethylated nacural fibers (cot ton) could develop into products of major importance. AN is produced in various countries of Europe, Americas. Asia, and Africa. The major producers are Western Europe, U.S.A. and Japan. The whole present production is estimated to be 2,8 million tons per year. The monomer may easily be absorbed by inhalation, ingestion and through intact skin. It has long been known to possess a high degree of toxicity, which has many of the characteristics of poisoning by cyanide ion. Several studies on the toxic effects in a variety of species of experimental animals have been performed. Some value of the toxic effects produced vhen given by inhalation arc listed in table 1. TadlK I - Toxic effect! pri doted by AN Riven ty inhalation, on aifftreni animal species (trom Pa rT , 1965). Aniaial Cor.ee ntrition (ppn) Reapers* Rat 36 Fatal after 4 hrs. exrr- r-r* Rat 129 51i;ht transitory effect* Hat 97 Slight trar.aitbry effstt* Rabbit 258 Fatal duri.-v; or after expciurs Rabbit 133 Marked transitory erfett* Rabbit 97 Sli.tht transitory sffests Cat 276 Karkedly toxic Cat 152 "arteeily toxic, scitetmes fatal Guinsa pi; 576 Fatal dunn; or after exposure Guinea ci; 267 Slight transitory effects Do; 110 Fatal to three fourths of th* does Do; 98 Convulsions and eons; no death Do; 55 Transitory paralysis; 1 do; died 29 Very slight effects ASI-PR 0002663 Vol.SS.n.6,1977 f carcinogenicity bioassays of acrylonitrile r 40} Ojralljv [he LEW in the mouse is of the order of 35 mg/Kg; in the rat, about 78 mg/Kg; and in the guinea pig* about 90 mg/Kg. Rats ingesting 0.1 per cent in water for a period of 13 weeks showed, retarded growth and emaciation^jorne,edicts w,er,e also,noted with as low asj?.Q5 pef cent in water in 2-year feeding studies. There is considerable, variation in resistance to acrylonitrile exposure in different species. Guinea pigs seem to be the most resistant to the toxic effects of acrylonitrile,, while dog? are the .least resistant. Toxic effects .of acrylonitrile which have been noted in animals include damage to the central nervous system, lung, liver and kidneys. When administered to pregnant'mice, acrylo nitrile'has. been found to be enibryotoxic (Sheufler, 1976). In manT.AX is toxic by inhalation, oral ingestion and skin penetration. _ It cjuses a sequence of symptoms whose gravity parallels the degree of exposure; weakness, head-ache, sneezing, nausea, abdominal pain, vomiting, loss of cons ciousness and asphyxia. It may also cause skin irritation, particularly when the skin' is exposed' to clothing or shoes wet with the chemical. AN, in contact with the surface of the eye, produces severe irritation or mild burns. The following population groups may be potentially exposed to AN; 1) workers engaged in- the production of AN monomer; -------------------- 2) workers manufacturing and processing AN products on an industrial scale; 3) residents around factories producing AN and AN products; and- 4) to a much lesser extent, people undergoing' contact 'with- AN products and materials containing these products, and finally; 5) consumers of food stocked in material made with-AN plastics. Until 1974 there were no available studies on the carcinogenicity of AN. At tliat time a project of long-term carcinogenicity hioa.ssays on rats was planned. The project was supported by a group of European Producers of AN (European Study Group for AN toxicity) *. Tne research was started at the end of 1974. 2) Planning, material and methods Our project includes experiments designed to study the long-term effects of AN, administered by different routes (inhalation and ingestion), at different concentrations (when given by inhalation), on rats. The chambers for inhalation exposure are basically built of seamless steel and glass. Tne control of AN concentrations is carried out by g3s chromatography. For the with a stainless steel stomach cube. * Rhdne-Poefesc. Ufir.e Kuhlman ; France); BASF, Bayer. Hoechst (Germany); DSM (Holland); Montedison, ANIC, SIR-Rumianea (Italy); BP (UK.). ASI-PR 0002664 rr 404 MALTONI. CIL1BEATI, Ct M.MO MeJ. L;-.o'0 AN was supplied and analyzed by the Central Laboratory of Montedison (Italy). The impurities and their levels in the AN employed were as follows- Acrylonitrile > 999<^> Acetonitrile Traces Acrolein Traces Hydroquinone monomethyl ether 100 ppm. The experiments utilized Sprague-Dawley rats. The animals have* been bred in our Institute for years, and whatever their use, are all examined at death by complete autopsy, giving us extensive information concerning their current pathology. The animals were weaned and classified by sex when 4-3 weeks old, at which time they were numbered by ear punch and divided into croup by litter distribution. After weaning, the animals were fed, ad libitum, with an adequate commercial diet. The animals were kept in groups of five, in macroion v cases, with tops made of stainless stud wire, hut, during the period of mlwlaiory treatment, they were housed in groups of ten in scainless steel wire cages with a solid bottom of the same metal. A shallow layer of white wood shavings served as bedding. The animals were kept in a temperature-controiled laboratory at 19-20* C. Two experiments were started around the same period. The plan of the experiments is given in tables 2, 3. Experiment l (BT201): studies the effects on rats of infulation exposure to 40, 20, 10 and 5 ppm of AN, 4 hours daily, 3 djys weekly, for 12 months. One group of untreated animals served as control. Experiment 2 (BT203): was designed to evaluate the effects on rats of AN. administered by stomach tube, in olive oil, at a single daily dose of 3 mg/Kg body weight, 3 times weekly, for 52 weeks. One group of animals, receiving olive oil alone by the same route, and in the same quantity, served as control. The animals were controlled weekly, and weighed every 2 weeks during the period of treatment and monthly after the treatment was over. All the detectable gross pathological changes were recorded during the control. All the animals were kept under observation until spontaneous death. The animals, when moribund, were isolated, in order to avoid cannibalism. A complete autopsy was carried out on each animal. Histological examina tions were performed in the Zymbal glands, interscapular brown fat, salivary- glands, tongue, lungs, liver, kidneys,.spleen, stomach, different segments of the intestine, bladder, brain, and any other organs with pathological lesions. 3) Results and comments Both experiments have now ended and complete examination or biological data and of the histopathologic material has been performed. polycarbonate. ASI-PR 0002665 'Unt.i: 2 J-; HT2IJI: Ivajuisnrc by ini',A.limit in Airxluiuiulc (AS) in air aI 40. 20. Ill, J pfiiii, -I fitnin ihnly, i ihiyt irerMjr, for 12 uuii:t. Results after tth wctli ft ml of the i-hfuituicnt). I i : limbi' i Hi, \ II in IV V | tnlni -- ------ <T~ I. t*ti 11 ro pia' Hr M .... 1 it wt - s1 1 ft* u i* fitinu - (Curilrala) r~ tMtwjr 1ku 1/ wld i H**. M'lft . . 1 ul f 1 uiart :fl e y *f .V 0* 9 and if 30 o ft V> * CO 0 if t y 4h1 0? a if y And if. 30 Jo CO > io 60 St J; 0 and (fi 10 *0J CO *00 Car r liu*i "I !) X x tii. x tr a' - . ji ;( fj mj ; n'C ht U. l*'l f n. i 6 i.i 1 i'. i 4 > Jti 14 -i. j 7 *>. i i. i t 11.1 It 31.j -1 Iri.ft t la.a 1 1.1 S 10.0 Avsrrnj*x 1 !*' (*!'-* ij (cl r**. t M ,* w>. II.* n,* 10/. 1 114.0 10 i, 1 ov. ? *4.0 1 If.O IOC .* 1( 4< AH tin. tucaui'f/ MRlT-ll 1.4 1.0 1.1 lit 4.0 4 .0 1.4 1.0 1.4 1..' 1.? 1 .0 > .0 1.0 --*------- y 4WIVA -| ftlTH tr sellit 'j ----- r---- "TT- . IllUMUM J l lUltHCrt 111 i(ii k ;|H *i hb|ilMti>tr.>iail HI.4 I J III Ch'j ariai.H `1 1* lM 'rt, 4v ihyv i witni jf f. (kl 4 1 Hu i {* A ) S. KM ft..* 11 lui-mi n/ Mltiaui k'l tfMfo :m> ricjr H4. > n.i l.a<> l- leal u.-+4\ n*. A', hAj44 1 (c| M ) ' * Sh,*t `=4.1 4.4 #> l..i\ 71.0 (Vi 4 1 T`i Ml 1 fc|` J|i j>f tlo. t Ik) ( --h-1 (c> -- - ! lif.O i *n. ( h 1 1. 1 lO-.O 1.0 - ./ . I j. i 1 *.n *6.0 m.i l.c Is' -- - '= U>.o 1 10.7 ;'..o . . 1 i. l 7^.0 4*0 i 1.1 71 6.6 i | 16. 1 4P.0 W.l J 21. 1 io;. i . * ). 1 114.0 1.0 t . 1.0 i *.o 1.4 - - f' i.o T. - r1 )*.0 1 *o 4-1,1 I.o " I---- - i1 -- - 1 1.6 . n 1 1. 1 IOI .0 1 1. 1 104.0 a 1 1. 1 101.7 1.4 - -; r 2 1. 1 10 - . * 6 20.0 *1.0 1*J 4 i i.i *l| i.o - - -- - - - - - ;* - 6 10.0 Si.6 1.1 i ; 4 6. w Vi'.fl i.o ' - - - 4 11.3 -1 6.6 91.0 1.0 r 1.0 ). | `.nip 1 i l.'l 1 iv.b ? l.i 1.0 4.0 1.0 -- - -- - - _ f i : * i (;i) Alive animals atier 2 wevks. w|tcn line fiisi iiiiihhii (a iiumngiy caieiimnsaj was observed. >' (b) 'J'tie |scrumants ate rcfcriuf to (lie unreeled tutml ter. fl i1 (c) Tire 1.1lusty lime of nuimnaiy tumours is given as age; the Iatthey lime of lire oilier lumoors is given as jKiit^l frurri ilie siarl of ilie experiment ASI-PR 0002666 i Tjuii.k 2 lixfH'rimeut BT20I. liklmstirt: by tiib.ilulion to AerytnmtiHe {AN} in air at VO, 20, JO, } t>tn, 4 hours daily, ) days weekly, for )2 weeks. Itcsulis after DC weeks {end of the experiments). i- i i -t t (tecond pari) Liuour Nl*. 11 *Mfcl OiNiAl !**> i Aa'-ror." 1 iLt-avj Bu li>f *>Mvk-t) r*> 1 i i 1 */ .7 1 1 i.j 1 ~ lo l.u ]| _ _ 1u J.ll i>. -Ni in ' -- " T Ii.(, MM i !. 1 1jO.Q i I, `i-.o 1.' i rf ,o * tail* t M. (Ci lOt.iACf fcl MM u-i * f,.t. J.) r1 i 1,) i 1.6 -- *1.1 M.o 4'4.<1 - *' W Til TlKOUKS |.ACM|inU<r tuMura Nt;>:?L>pua (ill HhUi fi Uo, (*) lAL<:ACjr It* Ml <> INljrtKMM'4 iktfl))VIO A* r,a ' Ar 1*0' X. 1AivDC/ i Itl'ACj 1 U*t (4 life a) Ua. o*t lll'J (l) t M. 7 (..L, Ui ~ 1 1. i 1 ).r< - 4i.li -- -- - - 4:.1* - - -- - - Us - - -- ,- - -*- rtn.u - - -- j- ' - M.4| - __7_ - ; -P-- - - -- - -- - O'.' ora itarrtl):* tait-rif/ U- DM (i.it>i 1 . -j - E - 1- - i Sku ciRintata u>. i .(b) u* _Tj_ t M) 1).) i Kl ). i i. 1 icljo KO\0 U) ; I.i - ,1.6 Ik) ). J ~i SI jo hi ' [ ' \ UlariM careiMMi Olhan* TOTAL to No, (N) \ i.i Avaraa* laiaocf iiav (iks) to M}7.0 M. (N) l No t:> b (i i N6.C 1 40.0 5 -------L------- 2 o.i 1 2.0 ,4 "to ju n. i J.6 i`i. i M i ]i ii, J U *i. i 1 ii, fci . ; i5.t 1-J >05.0 1 ink i% ii i.i 4T, u> :a.' 1)0 _*- - -4 -i J----------1 - ----------T~ . -rU. - r- , - * -- -- -- - - -- - - - -: -- i 1 1 t,G - t i*\ l 1. } - tt, ft l}o 1 Lii'J,.1 K ,i k Ki.O f . .. 1*1 . ?i. i \ 2*-* ]t in) 1u.( H 1 iT V- 1 i5.t II* |4 (si V* i __J______ ii iri i!i. H 4 Is1 i1:1 1 i -4-- i l>.u ).l H>.L> 10.JI t.4V (.1) M (0 (i:l Hi) (i) II) In) Im) I ini;niiul. | It II ill tin- 1-liC. 1 i II I II I I iimmIIjiv. I ni.i\ill.iiy. 1 I |i.n.Hnnl.il; 1 iitjiiiiii.il; 2 iimr tin* amis. ) Ilium,u n) skill; t sill h 111.11111 his ill >i i11 m mii.1, t iiiliiii.ll ,l. I. l n h .1u iiii.i. Isi|tl,lliII s.11111.11 l.lli111. H11.1 i ilI il,|i l|Itl; l. h 11k.1il111n.. ^ t SI |Ih III.HU INIS I||HI|||.|; | S|t|i,l H *ll I.I III )lV|H*|ltiyslS. i Hi il'IH H .111 II I* Hll.l 11) HV.liy; i It l4. .ll'llli.l ^ I /viiiImI i'I.iiiiI Hilt III hii.i; I liliiiiiiM III -1.111, t III III Mill HI III I.I III skill, I miIhuI.iii.hhh lilmis.ui hum. i li|min.i III .11 |Ih- i.hhiihi; ?. ItHik.ii'iiiiiis I / yii4i.it |-In I ,u I. in ii 11.1, I Mjii.iiiiiH i tliil.ii i ,iii iiiiiiii.i nl siiHii.ii Ii, I .iik'iiiH.iit HiiiiiM i*f ji.uit ii .is; J tiiln n.il .iili'iiimu; I 11 it i .1II It 11 II III II11 tif ns .11 y, I lit ii i i.myii mi.i lit lilt ms; I hi in Hill ,t Hii.i nl minis, fll) I Slits III ,|III t HIS lliili l.lliyli IS,|l | i iltt.l; 1 III |4ili*l4.lsll Hll.l, I .lillill.il (Ml IilH IIIM; 2llttlt'lljl JllclUMIMs; fji) 2 .ill. III.Ill is lit liv|Hi|'liysis; I .iilitii.il .iiliiiiiiii.i It)} I Mil h iii.iih mis :ii ijin ii 11 .i; I miIh nl,mi inis lilii n.iiij. iiini.i; 2 .nlitii.il it. I. iiik .lit iiiiiiiias. (r) I liliiiHiM ut skin, I siiIh ill.Kit mis hlmiintj; ;hij;|i is.it it ill i.i. 2 .ntlui.il .itli'IHiiiMS. (i) StVtl.il .lllilll.lls VII11 2 ill III! H C 11 until IIS. 2itHlk.lt IIII SIS. ASI-PR 0002667 J -) | li .. ! . * !................... !.......... Taki.i: J - i.\/Hiiincut Hi 20}: ItpoMiic by ingestion (lhn/i.n h tube) to Aerylmtitrtlr f/liVi injinx nil ul S ina K'g body mibt, } timet weekly, for )2 weeks, ( | TUvalu ultt'J Ul uveki (end u/ ffijr ex/h-iintent). 1 | .1 > 1 1 'll uhuuim |W* 1 1i' ii (npraftu*- tflMTMJtT tBl<i| HtUy 12 i 1 1 , J i k* util M alai 1 Corrao^ 1 bon __!i. i i luntOi (ha) S 3** k Ho. 1 lari ik**- tcr i M*. (a) 1 i 1 ii j 1 i'' H------------ j---------tniati.-i airii ___ ii__________ ___________ !i________ L***~r' - ura ! . i 4v*r^o* .'ail hu i__ 1 rilrruai*4H*"'* <*pnl fibromas Hi ulotypsi i CureinoMi 1 if it (aeka) Jr 1-aHiisrv animal Ha. AvciLfti Mann Ho. *M luketwji 1 ia|i of luoaun/ Mo. - 1 tvs-ra^ (loan Mo. y Ul 1aU-Ai| time J(uuun/ <*H (meeka) animal i i ~:!! in r broaktimM*" anft tan^iiwati. Avtiaye Jan ;u>. i Mo. i (il laiu^ry Ull tiat u"u*M1 / (meek a | aniaaij i AsL.. i_J cl_ <c* s 40 [ 21 5? .5 1*1.11 1.4 1ft 41.1 7.4 7 5.0 * tl.O 1*0 f 7,5 1 106.4 1 1 S r./r-c *2 ; o* , 40 40 ? 1. tl .0 2 5.1 ai.li 7.0 -- ,- ; 4_ l - Q 0fi4 0* CQ to 21 ?t .* *>0.? i 1.1 70 25.1 1.1 2 2.5 i *1 .0' j 1.0 1 i.J ; toa.b i>.j; 1! i v i 75 1 11 44.. ;6-'i Hon* 1 (Cantrala) 1 J ! 2 2.~ tTl.J and ii i ! 15 32.* i , 2* 14.i 1.9 4 '2 7.7 21_ 1.0 tii ' 73 17.: ft 4.6 1.4 4 5.1 i""> i* - 4 12* J -71.5 i 7.0 f i 1 4.o ; , ta. > - 1 4 - jl.O 1 7.0 - *6.6 l* t l.i ! Total i 719 229 l _____L_ \ \) J___ 1 i| -s ii) Ativc animals after 28 weeks, wlien die first tmiKiur 1a maim 11 ary carcinoma) was observed. b) ri-- (wt ceillagcs arc refer led 10 die a nrtiled uikiiIhi. c) 11k: latent y lime of mammary lumutirt is given as ant, die latency lime of llie oilier iumouis is given as period from live slarl of llie experiment. 3> CO f "D 1 ,1., " 000 i Tajii i. J - lixjH-rimrul lil'20i: ]'x|>hmiic by inyetfmu (i/hiiim ! lube) lit Acryltmilrite (AN) in itlire nil at i wg/A'g body weight, } times weekly, for i2 weeks. Kestilu iijltr HI weeks (eutl of Ibe experiment). (fttil pari) LWrUJ . <KJ. 1 II boa* 4 mr/Kf. 12 utkm util M olai i Cormc^ 4 **- Ur Ho. Ho, Sen 1 (-) alarl 40 40 21 A*ir*|i IciK) * fi Kim* lcki) (O s?.* I'M . -an of I'npur j iiaimi t Ha* 1*4 1h miwL* ITh TOUCHIMS Ha--a n turn ura Hut k tin** Hvi ihhI fal>rr*nna Corel nonaa AvetMte Xton Ho. UillftC Mean Ho. % (M taltnuj linn of kuMouro/ H*. (S) loicncf tine of tuHon/ (ou. ha) niMl (et*rku) mail ..to *12.) 1.4 2 5.5 61.0 1*0 tibroMeuonmi and urufuiMt, AwrOf'e *i*ll fit*. Ho. * <ti lotanrj of IIM tuauura/ (*ataj onmat 1 i.s lOfi.J 0.5 if 0* - 40 40 a s. tl.O 1.0 7 i.i fll.O (.0 -- - - -- -- (J and 0* to CO 21 *0.2 1. 1 20 25*1 a?.6 1.1 2 2.5 61.0 1.0 1 1.2 tofl.o 0.5 Hon* (Control*) i tf IS 11 44* 6*.6 0* n 14 j 2.' n.j Q mad if IW 14* \S a ?. 4 1.4 24 l*.i U5*f 1*0 2 ;.t 11*2 1*4 ft u.: 64.6 1.5 1.0 1-4 4 5.) -- 4 2. f 11-S 11. s 1.0 - 1.0 1 4.0 -- 1 2.0 66.6 - 66*6 l.f .l Tia lOl 2ii 22** (a) Alive anim.iU after 28 weeks, when the fmi iiininur la mammary carcinoma) was uliservcj. (I.i Tire |H-icttil.i|;es arc lefei red lit lire rut reel lit immln r (c) 'f lw latency time of mammary Inmotirx is given as age. die lalency time of lire oilier inmutirs is given as period frttm (lie start of lire experiment. ASI-PR 0002669 .........._c c Vol, 63, n, 6,1977 carcinogenicity bioass \ys of acrylonitrile 409 Under our experimental conditions AN, administered both-by inhalation and ingestion, had shown no ejects on the survival and body weight of the animals. No regressive histological changes had" taken place in liver, kidneys and lung. As far as neoplasias are concerned, their Incidence in treated and controls groups of inhalation and ingestion- experiments is given in tables 2 and 3. Several types of tumours have been observed. Among the most frequent there' are mammary tumours, Zymbal gland carcinomas, forestomach papiiIomaY"aH3'-acanthomas, encephalic tumours, skin carcinomas and uterin carcinomas. Mammary tumours. A moderate increase of* mammary tumours has been ob served in both experiments, in the treated groups, however without a clearcut dose-response relatiflnShTp^and "significant"'shortening of the average latency time. ---------------------------------------- -- Zymbal gland carcinomas. Only a few of these neoplasias have been observed. ' On the whole, the distribution in the "treated and control groups is not significant. " Forestomach papillomas and' acanthomas. A moderate increase of these tumours has been found in the treated groups "of'bocFf experiments. Encephalic tumours. As far as these tumours_are concerned, a systematic histo logical investigation on serial sections~has been performed on animals in the treated groups as Avell-es-in-the-control groupsr Systematic histology was made necessary since these tumours' arc not grossly detectable. These tumours have been found in AN treated (BT201, BT203) as well as in control animals, treated with olive oil alone (BT203). All the 4 tumours observed in the treated aninuts and 3/5 of the ones in the controls were gliomas (Fig. 1 and 2). s. 1 Encephalic glioma in a rat exposed by Fig. 2 - Encephalic glioma (peripheric area) in a halation to 40 ppm of AN. -rat- -exposed--by- inalation to 40 ppm of AN. E.. X 123. H.E., X 125. ASI-PR 0002670 4l0 -- MALTONI, C1UBE1TT, 01 MA10 - N-r#ci :: _; . ' r a". Mfj LatorO Two data have to be underlined. - -- 1) The -Xtumours observed'in the animals treated-with AX by inhalation ' have been found in- the animals treated .at. the .highest doses (40 and 20 ppm);................... ... . . ~- 2) The incidence of tumours in control animals (experiment BT203) has . been surprisingly high. - --- . . - -..To,,our^knowledge,: there, is-no:adequate systematic research on the ' * spontaneous incidence of tumours of the central nervous system in e.vpe- . - - rimental rodents. . . _.. , . .. Therefore, histologic .research has been extended .to comparable con- . - ittrol rats oLuncorrclatcd experiments, not treated at"all. Over`405 examineJ rats. 13 tumours have been observed: 4 gliomas, 2 ependymomas and 7 meningiomas. . Skin carcinomas. The onset of a few skin carcinomas has been found among the-animals treated by AX, administered bv inhalation. Uterine carcinomas. On the whole there are no significant difference among treated animals and.control groups. _. . 4) Conclusions On the basis of the presented results it may be stated that under our experimental conditions, ANT has shown a border-line oncogenic effect. At present our data do not make definitive evaluations possible. On the other hand, they point to the need of further investigations on the long-term effects of AX. Tn particular the following investigations are foreseen: 1) the study of the effect of AX, given by inhalation and ingestion at a single dose level chosen on the basis of our'present knowledge, on large croups of rats, with adequate controis; 2) the study of the effect of AX, administered at least by one route (possibly -.inhalation), on animals of another species (mouse);-- -------- ,, . 3) a histologic research on a large number of untreated rats of our breed to better . assess the spontaneous background incidence of encephalic, rumours. .On a_ i : wider scalei' this' type1 of study' should be ixtinded- to' other rodents"com- monly used in experimental bioassays, since our knowledge in this field is rather limited. , ; summary" " " ' ~ ' The present report deals with the results of long-term caidnogenidty biosssays of Aaylonitrile (AN), which lasted more than 130 weeka. The monomer has been tested on rats by inhalation (40, 20. 10. 3 ppta. 4 hrs daily, 3 nines weekly, for 32 weeks), and by ingestion (3 mc/Kg body weight, in olive oil. bystomach tube, once daily, 3 times weekly, for 32 weeks). A slight enhancement of the incidence of some tumours has been reported and com mented. At present no sound conclusions can be drawn, on the basis of the present data. The need of further research is s:ressed. ASI-RR 0002671 Vol. 68, it. 6,1077 ( caxclnocemcity bioasjays of acbylomtjulc f 411 RIASSUMTO Malto.m C. CiLttUTl .Ar. Dr Maio V. -- Saggi ipertnrentali di cenccrotrmot* Jril'Acnlorttirile, sommieutrato per injlezione e per mtestiooe, tul ratio. Vengono riferiti i risukati Jet unti dr canccrogcniciiA a lungo tcrmine 'JeH'Aeriionitrile (AX), durati piii di 130 settimane. 11 monomero e itato saggiaco su ratti per inalaziona (40. 20.'10. 5 ppm. 4 ore al.giumo. 3,volte. alia aettimana, pv.32 semmarig), o per ingggtjone (3 m;/Kg peao eo'rpored.' ih' olio di~ol!Va. mediant* utada'gastric*. 1 volta ai "giorno, 3'volte alia settimani.per 32 setti.-nanel. stata osscrvaca e valutata una modtca incident* di'alcuni tumori. .41 momento present*, sulla base delie ruultanze presentate, non possono esscre tracte concluaioni derimdve. Viene sottolincata la necessity di un jtiano di ulteriori rieerche. REFERENCES SoucFUx H. <1976U-BioL Rundach., 14. 221-229. 'S e, ASI-PR 0002672 ,iu moms en ce qui conceme les angiosarcomes et :s neohroblastomes. ast affectde par la longueur de . exposition au CVM. La comparaison des resultats obtenus chez le iat de deux differentes lignees (Sprague Dawley 3T1 et Wistar BT7) suggere actuellement que le faceur souche affecte de la meme fag on la reponse 'joplasique. La survenue de 4 angiosarcomes extra hSpati-ues, d'un nephroblastome et de 4 cancers de la , ande de Zymbal dans les portees de femelles ex,:sees au cours de la gestation pendant 7 jours, .mole montrer un effet transplacentaire du CVM. u'observation de quelques cas d'angiosarcomes sifiants suggere une nouvelle orientation dans I' in'prStation pathogdnique de I'acrosteolyse des .vriers exposes au CVM. Pr LATARJET - Les tumeurs mammaires ont-elles ete observes chez les femelles seulement ? Pr MALTONI Oui. Or ZAJDELA - Dans quelle lignee de souris 7 Dr MALTONI - Souris Suisse. Dr ZAJDELA - C' est une lignee que vous elevez chez vous ? Pr MALTONI - Oui.depuis 1963. Dans nos conditions d'experience, le chlorure de vinyle, lorsqu'il est administre par ingestion (gavage)(tableau 19), produit chez le rat des angio sarcomes du foie et d'autres localisations, des nephroblastomas et des cancers de la glande de Zymbal.On soulignera cependantque les doses produisant des tumeurs sont tr6s elevees.lorsqu'on les compare <t I'exposition possible chez I'homfne. TABLEAU 19 Experimentation BT11 : Exposition par ingestion (gavage) au CVM an huile d'olive, k SO, 16,65, 3,33 mg/kg poids corporal. une fois par jour, 4-5 j./semaine. 52 semaines. Rdsultats aprfts 104 semaines. GROUPES ET ANIMAUX (RATS SPRAGUE- DAWLEY) TRAITEMENT Total Survivants 1 . CVM 50.00 mg/kg 80 6 Carcinomes de la glande de Zymbal N. 1 ANIMAUX AVEC TUMEURS Nephro blastomas Angiosarcomes Foie Autres locali sations Carcinomes mammaires Autres types et/ou localisations (c) N. N. N. N. N. Total N. 1 13 1 (a) 3 4 (d) 22 (g) II CVM 16,65 mg/kg 80 10 1 3 8- 5 1 (e) 15 (g) III CVM 3,33 mg/kg 80 20 - - - 1 lb) 2 2 (f) 5 IV ContrAls: huile d'olive 80 13 - - -- 2- 2 Total 320 49 2 4 19 2 12 7 44 a) 1 angiosarcoma du thymus. b) 1 angiosarcoma intra-abdominal (prds du rein). c) Des cas da fibroadSnomes mammaires et de tumeurs surr6nales et pituitaires (g6n4ralement adenomas) n'ont pas ete pris an consideration,' leur distribution dans les diffSrents groupes n'etant pas significative. d) 1 carcinoma cutane sebace; 2 papillomas du pre-estomac; 1 adenocarcinoma intestinal, el 1 lymphoma. f) 1 sarcoma sous-cutanS avec compos ante angiomateuse; 1 sarcoma intra-abdominal ossifiant avac compos aite angio- mateuse. g) 1 animal avec 2 tumeurs. ASI-PR 0002673 Au moment de mettre sous presse ce compte rendu debut Jut Ilet, on pouvait disposer de donnees de I'experimentation 8T 11, a la date du 21 Juin, c'est -a-dire 120 semaines apres son debut, alors que i'experimentation en eta it presque a la fin Compte tenu du grand mteret'de ces resultats on a juge important de rapporter css derniers resul tats (tableau 20). f seulement 12 animaux survivants). TABLEAU 20 Experimentation BT11: Exposition par ingestion (gavage) au CVM en huile d'olive. & SO, 16,65, 3.33 mg/kg poids corporal, une fois par jour. 4-5 j./semaine. 52 semaines. R6sultats apres 120 semaines. GROUPES ET ANIMAUX (RATS SPRAGUE- DAWLEY) TRAITEMENT Total Survivants Carcinomas de la glande de Zymbal N. ANIMAUX AVE.C TUMEURS N4phroblastomes Angiosarcomes Foie Autres locali sations Carci- names mammsires i Autres types i et/ou 1 localisations! ,, N. N. N. N. N. N. 1 CVM 80 2 1 2 16 2 (a) 5 7 (c) 29 50,00 mg/kg II CVM 80 2 2 3 9- 6 3 (d) 21 16.65 mg/kg III CVM 80 4 - - - 2 (b) 4 3 (e) 9 3.33 mg/kg IV Controls : hui le 80 4 1 - -- 4 5 (f) 9 d'olive Total 320 12 4 5 25 4 19 18 68 a) 1 angiosarcome du thymus ; 1 angiosarcoma intra-abdominal (pres de la rate). b) 1 angiosarcome du poumon ; 1 angiosarcome intra-abdominal (pres du rein). c) 1 carcinoma cutane sebace. 1 hepatome ; 1 angiome du foie ; 2 papi Homes du pre-estomac , 1 adenocaremome intes tinal ; 1 lymphome. d) 1 angiome du foie, 1 carcinoma surrenal ; 1 lymphome. e) 1 sarcome sous-cutane avec composante angioblastique ; 1 sarcome intra-abdominal ossifiant avec composante angiobiastique , 1 papilloma de la vessie. f) 1 carcinoma cutani; 1 papil lome du canal auditif ; 1 carcinoma de la vesste: 1 carcinoma surrenal; 1 sarcome reticulaire. g) Plusieurs animaux avec 2 tumours. De leur analyse on peut tirer actue/lement que/ques conclusions ; En comparant les resultats obtenus dans les groupes trait is avec 50 et 16.65 mg./kg., dans les 1) A 50 et 16.65mg./kg., le CVM produit des angio sarcomas du foie et des nephroblastomes. qui sont les deux tumeurs les plus typifyjes produites par le monomere. 2) A 3.33 mg./kg., les 2 angiosarcomes observes avaient une localisation extra-hipatique. 3) II existe une relation tres nette entre dose de monomere et la reponse tumorale.avec une chute entre 16.65 et 3.33 mg./kg. groupes traitis avec 3.33 mg./kg., et dans les temoins. la dose de 3.33 mg. /kg. dans nos condi tions experimentates, semble avoir un effet card nogenique border -line* Aucune tumeur n'a ete observee jusqu'a pre sent, c'est-a-dire a 57 semaines du debut de I'ex perimentation, dans les animaux traites avec Img/kg. 0,3mg/kg. et 0,03mg/kg. (experimentation BT27). Cette derniere experimentation fut commencee au moment ou I'on observait les deux premiers angiosarcomes dans les animaux de /'experimenta tion BT11. traites avec 50 et 16.65 mg./kg. ASI-PR 0002674 26 cc larch 15, 1978 CONGRESSIONAL RECORD -- Extensions of Remarks EIC09 viet Jews and to allow all Soviet Jews to Tho Turks retaliated by closing U.S. In space to recount, that the State Department erclae their right to emigrate. telligence Installations in their country. deliberately deceived Congress about humAQ Section 2. That this Board urges the appro- Thesa electronic listening posts monitored rights to Turkey. ' late otnclais of the Soviet Union to grant Soviet mlsslls tests and military maneuvers. Footnote: A spokesman for ths Turkish ' is Immediate freedom and the right to At Stnop on the Black Sea, for examnle. so embassy said his government would prefer to nigral* and he reunited with his wife to phisticated radar devtces could zoom directly eschew "polemics" and discuss "Issues" in latoly Shchamnsky as guaranteed by the on soviet missile launch sites. stead. Turkish authorities, he said, do not I elsinkl Accord, 1975; and that if the Soviet At the time the bases were cloeed. Intelli want to expel the Greek Orthodox church rthorltlcs bring Anatoly Shchoranaky to gence sources claimed they were responsible from Istanbul, and they do not tax the lal, that he be given an open and puhlie for about a fourth of the clandestine infer** church Illegally. With respect to passports, ,1al. and that prominent repretentatlves of matlon gathered about Soviet military activi the spokesmen said that all Turkish citizens aajor Bar associations and of the Criminal ties. American technology and ingenuity, are limited to a single trip out of the country jar of tbo United States be permitted to be however, hare produced substitutes for most every two years, la order to conserve "hard iresent throughout the trial of Anatoly of the Turkish installations. currency." He also claimed that the Turkish shchnransky.o Far more important. In the Pentagon's minority la Greece Is harshly treated. view, is Turkey's rots as the Mediterranean anchor of the NATO alliance. One worried general told us; "The big question is whether ^RISI TURKISH VIOLATIONS OP HUMAN BIGHTS they can perforin their NATO responsibilities without military aid. We get a real buy with the Turks. Gits them a few weapons, and you [RISK/BENEFIT DECISIONS AND 1 PUBLIC HEALTH buy a bunch of divisions. They'va got the HON. NEWTON I. STEERS, JR. or MABTLAXD manpower, and they proved they could u*s It In the Korean War." Our sources say that President Carter has HON. CLARENCE J. ER0WN or Ohio IN THE HOUSE OF REPRESENTATIVES adopted the military view. He has been IN THE HOUSE OF REPRESENTATIVES Wednesday. March. 15. 1975 strongly Influenced by the Joint chiefs, who meet with him frequently. In fact, the Wednesday, March 15. I97S Mr. STEERS. Mr. Speaker, this year, president recently boasted to bli Cabinet Mr. BROWN of Ohio. Mr. Speaker. S the House will be considering the ques tion of foreign assistance to Turkey. At ' the base of this debate is the question of whether or not the human rights rec ord of Turkey has improved. behind closed doors that ha "has generated a compatibility among the strategic planners of our government unknown in former administrations." He reportedly is preparing, therefore, to ask Congress to approve ths tl-bllllon de years ago. the Committee on Govern ment Operations issued a report on the regulation of food additives, particularly nitrites and nitrates, under the Food, Drug and Cosmetic Act A constituent of mine. Mr. George fense agreement that was signed in 1078 As a member of that committee, I sub Spring, has sent me an interesting arti between Turkey end the United States. Ths mitted additional views relating to the cle on this very subject that I would like to insert into the Congressional Record for the benefit of my colleagues. A "Deueexxte Whitewash** oh Human Ricirra in Tusjcit Stats Department soft-pedaled Turkish hu man rights abuses, our sources say. to avoid irritating a Congresa that is already sympa thetic to tha Greek and Cypriot causea. In any event, the human nghta reports on Turkey simply do not reflect the truth. Par arbitrorv effect of the Delaney clause on the Federal Government j 1* ^pro tect the puuuc ueaitii and saieguard CKe Nation's food supply. In those additional views. I specifically (By Jack Anderson) ticularly galling to the Greeki is the state addressed myself to the need for a_risk/ The Carter administration Is so worried about declining Turkish military power that it bos fnlstfled its report on human rights practices In Turkey and has portrayed the country ns a virtual human rights paradise. The falsa account, part of the State De partment's "Country Reports oa Human Rights Practices." was delivered to Congress several weeks ago. The department claimed It had little 'conclusive proof" or "signifi cant evidence" to support allegations of human rights abuses in Turkey. A more enigmatic statement, worthy of master diplomat Henry Kissinger, was issued on Turkish-controlled northern Cyprus. Human rights questions In Cyprus, stated the report, "cannot be treated In Isolation from political considerations." There conclusions are dlsptued by the Stato Department's own files, which contain abundant evidence of the harsh treatment of minority groupe and political prisoners. Indeed, the Turke have a reputation for bru tality. which makes them fierce fighters and cruel Jailers. American citizens, who have had the misfortuno or landing in a Turkish lockup, have told of vicious beatings. A favorite Turkish torture Is to hatter the soles of a prisoner's feet with truncheons, which causes excruci ating pain and leaves him unable to walk. The Creek government, taking exception to the State Department's retry tale, lodged formal proteats both In Athens and Wash ington. And Cypriot Ambassador Nlcos Dtmitriou marched Into the State Depart ment and indignantly delivered an official letter of protest. The official Hew of human rights In Tur key. Insiders suspect. Is s deliberate white wash intended to tip-toe around Turkish sensitivities. Tbs Turks are still smarting irom an areas embargo Imposed by Congress sfmr Turkish troops Invaded Cyprus with M. weapons. ment that "there does not appear to be any beneflt_tra`de-oiTr rather than an arbi ofllclal discrimination agalnat Individuals belonging to minority groups" and that they enjoy, among other rights, "freedom of worship," There hoe been a history Of religious dis crimination against the Greek Orthodox trary approach, to.complex scientific and technological questions affecting our food supply. To quote briefly from the views rexpressed in that August 1972 commit tee report: -- 1 "~11 Church In Turkey. The best evidence can bo Ws nil want to assure that ths faod people found in the statistics; tha Greek Orthodox eat win not harm them. And. insofar as It is population In Turkey has dwindled from poslble, govsmmsnt should assure this. But 111.700 in 1929 to 13.500 today. A confidential It must be racognlzsd that absolute guar diplomatic document, reporting on the op antees may not always bs possible--and for pression of Oreeka In Turkey, cites these something ss big, pervasive and powerful as flagrant abuses: ths Federal Government--In an area where, A deliberate campaign of harassment has been reported against Greek Orthodox dertes surprisingly, so little Is scientifically prov able. in Istanbul, ths vory elty where ths head of ths church traditionally resides Greek religious leaders have been denied passports to travel abroad, sven for pressing personal In view of my position on this issue, it was with considerable interest that I re cently read the remarks of the chairman reasons. Editorials in ths Turkish press have - of the Senate Health Subcommittee on railed agalnat ths church. Following one the need for a Government approach to series of articles, demonstrators laid a "black these problems based on a realistic ap wreath on which wore pinned slogans asking praisal of the limitations of existing Fed for tho expulsion of the (Oreek Orthodox| Patriarchate from Turkey." Turkish authorities are cracking down on Oreek minority schools. Teaching of tha Oreek language haa been "aeverely curtail ed," and Turkish oinclal have refused to appoint principals to Greek high schools. Alt eral operations in the health field. In an address delivered February IS, 1973, at the Food and Drug Administra tion symposium on ``Risk/Benefit Deci sions and the Public Health." Senator Kennedy made a major contribution to repair requests in excess of SIS were refused ward moving Government policy on this last year. And ths Turks have begun assess issue off dead-center. Senator Kennedy ing heavy taxee on Oreek schools, though said: they are owned By chanty Institutions, which are supposed to be tax-exempt. we must begin educating the public to the reality that there is no euch thing as abso Last year. Turkish officials began "the close lute safety. Regulation can never completely surveillance of persons who visit tho Greek'' and totally protect the public. Largs teg General Consulate In Istanbul" and "sys menta of ths American public already accept tematically ask for (theiri identity cards." this fact. But It is time for persons in posi Leaders In the Greek Orthodox minority have also begun to "receive anonymous Ut ters, threatening tha property and lives of ths recipients and containing demands for tions of 1eldership to strengthen this under standing with mors candid discussion of ths limits of regulation. Senator Kennedy's complete remarks . Thera la other sridsnos, which we lack tho delivered at this FDA symposium held at ' ASI-PR 0002675 C( / E 1310 CONGRESSIONAL RECORD---Extensions of Remarks March 15. 10? the Air Force Academy should be read in their lull context to appreciate the co gency of his call for a new approach to an increasingly urgent problem. I com mend them to the attention of the Con gress. the Executive, and all citizens con posed -to asbestos, o< whom 300,000 may die of lung cancer. Approximately two million Americans are regularly exposed to benzene, 'which has now been demonstrated to be a very potent carcinogen. But clearly, these cases are only the tip of the iceberg. The real or potential dangers of peak of banning saccharin, when medio opinion le widely split on whether it mi ; confer potential health benefits. And we quite appropriately restrict t! US* of laetrlle. even for patients dvlrtg wit .known cancer. But we sllow millions r healthy Americans to be unwittingly expos* cerned about the present and future those myriad substances may not be known to a pesticide like toxapheae. which clean' health of the American people. until we bave much more Information-- cause* cancer In animals. I insert the remarks of the chairman whose collection may take years or even .. In most cases, these Inconsistencies are nt of the Senate Subcommittee, on Health at this point In the Becqsh. Hem arks or Senator Edwaso M. Kennedy generations. I am reminded of s story which Dr. Irving Sellkoff told last spring before our Health Subcommittee. When cigarette smoking was exclusively the fault of regulators. They ats reflect the contradictory mandates and In consistencies la regulatory law, which In turx are often the product of pressures by specie1 I am. pleased to be' able"to" Join you here first becoming widespread, a physician oaked Interest groups that are capable of swamping today at this symposium on risk-benefit anal a distinguished cancer expert whether the the public Interest. Congress has s specie: ysis in tha area of health, care. And I am ( practice worried him. Hot at all, the expert responsibility to review these laws to ensur - especially pleased to and a distinguished - replied. Cigarette smoking would reduce the they reflect the public's wishes. We cannot group Hits this, under tha auspices of the. smoking of clay pipes. And the smoking of tolerate a situation In which Inconsistent FDA. grappling with a subject which is off clay pipes was known, to cause cancer of the regulatory' -actions heighten the public's great Importance to tha public health and' ftp i confusion and skepticism. which is becoming mors current and con Zt took more than twenty year* of maailve With all these problem*. It Is no surprise troversial with each passingyear. experimentation with-cigarettes on.an un that America's public faith In government You have arailable at thls'conferenc# tha witting American publlo to demonstrate that regulation Is strained to the breaking point. main ingredients for dealing with a complex society waa the loser In that trade-off. Our private capacity to generate hazards to Issue of great public value. You have One Whether we are now losing on a comparable health has outstripped our public acuity to leadership from Don Kennedy of FDA and scale on any other substances remains to be evaluate and control the hazards. Doug Costls of FPA. You hare a distinguished seen. On* atep w* can take to deal with this tgtoup of participating scientists and analysts. The problem Is clew, but the solution. Is deteriorating situation la to commit more re And you also have the additional ingredients much lesa so. The American people have sources to perfecting the methodology of risk of distance from Washington and tna Ons, reacted by giving the Federal government benefit analysis. In particular, wa need more cool mountain air of this outstanding eet- a mandate to screen chemicals for hazards, research aimed at Improving our ability to ` ting. and to regulate.their distribution and use as evaluate the risks of chemicals. We must with these advantages already in place, drugs, food additives, or Industrial chemicals. reduce Uie'uhcerGlinty involved in these risk I am confident that your deliberations will But this I* only half the answer. For we - assessments, and we must make these assess help promote our understanding of more lack both the money and the manpower to ments cheaper and faster. effective ways in which we can use risk/ test all these man-made substances for all In particular, we need to devote more re- benefit analysis to Improve the public health. their passible consequences. Even if we could sources to perfecting alternatives to animal Especially at this time of growing challenge* test all these substances, available method testing s* mean of assessing the toxic po- to the traditional techniques of govern ologies could not tell us with certainty which ' tdntll of cnemleals. This work goes on now mental regulation, the effective application are dangerous to humans and which are at the Cancer Institute, at the FDA. at the of such; analysis Is essential tf we are to not. And even among the dangerous com EPA, and at the National Institute of Envi preserve the proper balance between free pounds, we would not know precisely the ronmental Health Sciences. But It Is research competition and wiss regulation in sensi rosxnttude of the threat. ' that needs better support and better coordi tive areas like health care. Thil uncertainty Is a central element_ln nation. I also detect a sense of urgency about the regulatory dilemma we lace, it is diffi In the long term, research on risk and this symposium that has been missing for cult to believe that cigarettes and asbestos benefit analysis will probably prove more im too long In discussions of . this type. I speak are unique in their enormous adverse pub portant than any other single step we can now as an elected official and as chairman lic efTects. But which other chemicals will take to Improve our capacity to protect the of a Senate Subcommittee whose prime re turn out to be the gross offenders? So far public health through regulation. It Is work sponsibility is the protection of the health of we can only speculate. There Is no such that will allow legislators and regulators to our citizens, t deal dally with the political thing as a simple, straight-forward answer. speak with much greater confidence when consequences of regulation and the people But we face the alarming possibility that they warn of tha hazards of a drug, a pes It affects. I am conccmcil-lhAt^Pur regula among tbs enormous number of substances ticide of a food additive. In this way, our tory--hma--uuhnritlr. ir y-mgtng gjoU that our highly Industrialised society la research work wtll enhance the scientific ' --* riist.me from the people. Our cit snewing into ths environment age some that "credibility of our regulatory institutions. izens no longer fully understand or trust even now may be causing massive cancer But research is a long-term strategy. There the agencies created by Congress to pro enidemtes for the current and future genera are also short-term solutions that are equally tect their health. And these negative de tions of Americans. Important, but more difficult. velopments come it a time when the num The dilemma Is also complicated tty our On* key element Is to improve the way ber of preventable threats to the public Increasing technical ability to detect the regulatory agencies set priorities. It is clear health. Is growing larger each day. presence of chemicals at smaller and smaller that FDA, EPA and other regulatory Institu Our major challenge--yours and mine-- .'., concentratl-ns. In our preset state of par tions do not have the people or the money is to enhance their atrengths and eliminate tial knowledge, potential dangers are every to carry out the huge Job assigned by current the weakneasee of these agencies and their where. but certain dangere are rare. We are law. missions. Port oL-tho .challenge la to perfegt the methodology of risk/ngnent analysis.. *'.so mat regulatory decisions' of the FDA, . , JpEA.and other agencies can-more accurate ly reflect our public goals. The challenge also requires us to do more to educate the public about regulation and Its limits, and to involve the publlo more directly in the regulatory process. I need hardly remind this audience of certain facts that underlie the regulatory dilemmas wc face today. We Uvs In an expanding sea of man-made chemicals-- drugs, food additives, industrial chemicals, and pesticides. - American induatry manufactures 70,004 chemicals a year.'One to two thousand new chemicals enter tha market annually. An average auto worker Is exposed each day to between 100 and 600. different chemicals. We know that some of these substances are dangerous. Stx million Americans are In the imnotsible position of walking through a minefield blindfolded, with t^s knowledge that the devices we trigger today may not ex plode foe many years, or even decades. Moreover, as science and technology ad vance. there are Increasing numbers of prod ucts and activities that pose potential threats to the public health. Recombinant DNA Is a ca*e in point. For the first ttme In history, scientists voluntarily ceased their work out of fear of potentially harmful effeets of their work on public health. That Issue has become s esse study of the pitfalls we encounter when scientists and public officials try to work to gether to apply the risk/beneftt calculation. In large measure, this difficulty results from dealing with a novel sclentlfia technique whose ultimate Implications are probably lmoossible to know at the present time. Even when we find that risks exist, how ever, tbe federal government too often treats But It IS not clear they are taking maxlt-mum advantage of the resources the.- now ..have. Our regulators need to plan better. .-They should publish and circulate more un derstandable plans and priorities for dealing with the multiple chemical threats for which they are responsible. This action win enable them to cany out their missions more effec tively. And it will enable Congress and the public to deal more effectively with the iso lated chemical hazards so frequently reported In the medio. Another key element In strengthening our regulatory approach Is Improved public edu. cation. Unfortunately, public education is . Often seen today as a tired and meaningless concept. It Is our responsibility to give it new life and content, public understanding of the regulatory process hae always been the cornerstoneof successful regulationTn tbe~past. ifid It will be essential for tbe success we regularly exposed In the workplace to chem them inconsistently. On one hand, we sub- hone to achieveTfTlh'e future. icals known to have caused esneer Id ani eldlzs tobacco-growing, and we ship tobacco W* must begin educsting the public to mals. One million Americans have been ex abroad as foreign aid. On another hand, wa the reality that there Is no such thing as ASI-PR 0002676 1 Tr r 'arch IS. 1978 CONGRESSIONAL RECORD -- Extensions of Remarks E 1311 V elute safety. Regulation can never com: tely and totally protect the public. Large I Tiients of the American public already < ept this ract. But It is time tor persons in '`siUont or leadership to strengthen this demanding with more candid discussion 1 the limits or regulation. '' .'his approach does not mean we should recommendations along these lines in Its study of EPA decision-making. We cannot overestimate the Importance of public par ticipation In regulation. It Is increasingly clear to the average American that there Is a large dose of sub jective Judgment in the rules which pour out of EPA. PDA, OSHA and other regula In. celebrating Hungarian Independ ence Day, we honor the courage and vision of those who led their people s struggle for national freedom in the last century. More than that, we remember that spirit of patriotism which sustained Hungarians in every age and which has re open the chemical flood-gates and let tory agencies. Even under the best clrcum-" flourished in our own time. The memo- tericans drift in the rising flood or toxio jstanecs. We should give the beneflt of the ubt to the public. Tlio burden of proof ould bo on those who profit from the eale chemicals to show that their distribution id use suould be permitted. stances, this subjectivity is inevitable. It re jies of the Hungarian Revolution in 1056 flects the limits of rlsk/benefit analysis and the realities^ of politics. It Is nothing to apologize about. But if decisions ore eubjective, then the. process by which these decisions are made , are still fresh and vivid in the hearts and minds of Hungarians, which is testimony to their acute desire for real independ ence. But we must be honest Id discussing the becomee of great importance. That process " The Revolution of 1848, even as that arts of our current resources and techques. Risk,'benefit analysis Is. after efl. ah iperfect art. Its application will necessarily .rare fallible. But the American people will accept this result and beLroore tolerant and supportive of regulation, as long os they understand the basis on which the decisions have been reached. Perhaps our greatest national resource le the Infornicd'Cotnraon sense of the American people. Inevitably, we shall encounter situa tions in which the known risks and benefits of substances are closely balanced. When these situations occur, and when citizens can control their1 own exposure to such sub stances. the correct approach Is to Inform tho public about the nature of the risks and benefits, and to let them mako their own decisions about exposing themselves to the chemicals Involved. Americans are ready for this responsibility. will not be accepted as legitimate unless It of 1956, aroused great sympathy m the Is open and understandable. And the way to make It open and understandable Is to ensure that representatives qf tho publle bare direct access to it. Regulation has become one of tbe foun dations of modern puollc health in the United States. The. legitimacy and strength United States. Kossuth's visit in 1851 was a dramatic occasion for celebrating American support for Hungarian free dom. Since that time countless thousands of Hungarians have come to America, seeking larger liberties. Today, there are of FDA and EPA sad other regulatory lnstl- . well over "a million Hungarian-Ameri tutions are national health resources. They deserve for greater emphasis and attention by Congress and the public than they have received la recent years, f look forward to the recommendations and suggestions of this symposium as a useful step In meeting the cans. whose contributions to our national life are outstanding in every area of en deavor including science and Industry, music, and the arts, journalism and entertainment. growing challenge. And I also look forward Mr. Speaker, on this special day I join to working with you. as we build a wiser with our fellow Americans of Hungarian and more effectiee future for our nation's descent in celebrating the independence system of public health.o that the great patriot, Louis. Kossuth, helped establish. However, it should not In faet. they are demanding It, as the lesson go unnoticed that the same Russian im of the saccharin controversy now makes Clear. A recent poll showed that 78 percent of Americans canttnua to oppose a ban on saccharin manufacture and that T7 percent of those'who use It plan to keep on doing so. By contrast. In the case of taetnle, the saccharin precedent dots not apply. As pro posed for use In cancer treatments, laetrlle Is a- drug. and. It should be held to the same THE 13TH ANNIVERSARY OP HUNGARIAN INDEPENDENCE HON. JOHN G. FARY or ILLINOIS IN THE HOUSE OF REPRESENTATIVES perialism that prevailed in 1849 is still present today and continues to oppress the legitimate aspirations of the Hungar ian people for real Independence and to be free of foreign domination. Let us pray that those noble aspirations are realized one day soon. strict tests of safety and effectiveness which Wednesday. March IS, 197S all prescription drugs are required to meet. We should also remember that the popu lation using lactnlo Is an especially sensi tive group. Cancer patients are 111 with a dread disease. They are much more prone to o Mr. FARY. Mr. Speaker, today marka the 130th anniversary ot the Hungarian Revolution ot 1040, in which the people ot Hungary rose up against tho domina HEARINGS BY THE HOUSE SELECT COMMITTEE ON AGING, DELA WARE COUNTY. PA, grasp at straws, and to choose a treatment without. pravea-effccUveueASiyspeclally when the alternatives are as grim as chemotherapy or surgery or radiation. As a result, these patients are entitled to a degree of regu latory protection which the average Ameri can may not require. tion of the Hapsburg Empire. Early In March of that year, the great patriot leader, Louis Kossuth led the national demand for parliamentary government. Just a year before, national elections had supported the movement for autonomy, HON. ROBERT W. EDGAR , , Or 4PENNSYLVANIA IN THE HOUSE OP REPRESENTATIVES Wednesday. March IS, 197S Informing the public, however, does not culminating the famous ten points. In mean printing s few lines In the Federal Register, while manufacturers flu America's living rooms with enticing advertisements for potentially hazardous products. Regu lators must tight firs with fire. They must start using the print and broadcast media td;, infarm'~the puBUc^dn . ways effective cluding responsible government, popular representation, religious liberty, aboli tion of serfdom, equality before the law and other principles basic to a free soci ety. These were adopted by the deputies ot the Hungarian diet on March 15, 1848, enough to make their'message heard and understood. In doing so, they must show a creativity and Ingenuity they have shown too seldom In the past. .They must make the esoteric concent of risk and benefit analysis underT* standablc to ordinary citizens be'using terms aiid'tiicy thereby became equivalent to a constitution. Tragically, the new government was to be ruthlessly suppressed by invading armies, which occupied Budapest In January of 1849. Resisting to the bitter .and tinaces which relatelo thcrfdiniVlTOt end in the face of overwhelming odds, This aspect of, public education Is essen the Hungarian diet proclaimed a republic tial to successful regulation In our Increas in April, electing Kossuth as "governor- ingly complex modern world. By this ap president." Tile republic collapsed under proach. public education will become a way of bivolving citizens.in regulatory, decision making. They will become partners In pro tecting themselves from potential hazards. We must also search for other ways to pro mote this public partnership. In particular, the combined assault of Austrian and Russian troops, but Kossuth escaped. Nevertheless, the people's will for free dom lived on. and in 1867. only 16 years after the uprising, the constitution of we must find better ways of directly Includ 1848 was restored peacefully and Hun ing the public In regulatory decisions. gary acquired responsible government. The Environmental Proteetlon Agency has After the First World War. the political considered experiments with public partici union with the Hapsburg dynasty ended, pation in Its regulatory process, and tbe Na tional Academy of Sciences recently mad* and Hungary became a wholly independ ent nation. Mr. EDGAR. Mr. Speaker, on Friday. March 3, the Select Committee on Aging, represented by Congressmen Mike Blouin and Davi Evans, held field hear ings In my district to gather testimony regarding the Older Americans Act, I participated in these hearings which, in my view. were quite productive. For the past few days I have Inserted Into the Rrcono portions of the testimony we re ceived. The ninth section follows: Bunting Friendship Fseesom House, INC, Darby. Pa, Tut House Select Committee on aging The Bunting Friendship Freedom House. Inc, would like to go on record as stating that tho Government is to he complimented for at least recognizing the plight ot its older Americans. We think it has been a long tune coming and even now, we have only scratched the surface. Even though we are providing health screening, socialization, recreation, nutrlous mtnls, nutrition information and lawyer* for the writing of wills for some people, how about the thousands we ore not reaching; tome who are stored sway In nurs ing and/or boarding homes, unfit for human habitation? There should be some mecna- f ASI-PR 0002677