Document rBqE5BpddM27KZ3VD7ppvR9ka

I# MONSANTO BIOHAZARDS COMMITTEE Minu tes of a Meet i n g Au gust 24, 1983 ' 'h Committee members present were: Dr. George Roush. Monsanto; ~ Dr. Leon Golberg, Duke University; Dr. Marvin Kuschner, School of Medicine, State U n i ve rsi ty of New York at Stony Brook; and Dr. Rober t E. Olson, Un iv er si ty of Pi ttsburgh School of Medicine. The meeting was called to order at 9:00 a.m. by Dr. Roush. C o r r e c t i o n s to the minutes of the July 27 meeting were as follows: on page 2, pa ra gra ph 2, line 21 the sentence should read "These CD-I mice also were affected by amyloidosis in the controls (76%) as well as the experimental groups (90%);" page 2. paragraph 3, line 3 should read,".... alarming to the Committee because it sug ges ted that the compound is a primary carcin ogen in that it pro duces un exp ect ed tumors such as those of the stomach and nasal turbinat es;" page 3. par agraph 1, line 6 the sentence should read "the overall view of the Committee was that the findings raised serious questions about the toxicity of Alachlor. The case for co nt i n u i n g use of Alachlor is based on the facts that ...;" page 3, last sentence, paragr aph 1 "The Committee requested a r e e x a m i n ation of all the data on worker exposure.;" page 3, paragraph 3, the last sentence should read "... as a step in obtaining a more ac cur ate v iew of the action of the compound." W i t h these a m e n d ments the minutes were approved. The first item of business was a continuing discussion led by Dr. T. Fuh re m a n n on the t o xicology of Alachlor a substituted c h l o r o a c e t a n i 1 ide (Lasso). Again in attendance were Mr. Robert Harness, Director of Environmental Operations for the Agricultural Products Company and Dr. Edward Debus, Director of Product R e g i s tration for the Agricultural Products Company. Mr. Harness reported that the top executives of the Agricultural Products Company, Mr. Donald Swan and Mr. Nick Reding, had given top priority to the registration of Lasso in the U.S. for expanded use whi ch requires the approval of the EPA and rere gistratio n of the product in Canada. A hearing will take place on October 6 before representatives of the Health Protection Branch and A g r i culture, Canada in Ottawa under the Chairmanship of Ian Munro. Prior to this meeting. Dr. Fuhre m a n n had circulated to the C o mm it te e a complete file on the properties of Alachlor. including its chemistry, toxicology, m e t a b o l i s m and data on exposure to workers. At this mee tin g he proposed to review the data on the inves ti gati on of worker exposure. He reported that 70 employees of the C o m pa ny had been examined for evidence of eye disease when the findings of uveal d e g e n e r a t i o n in pigmented rats was d i s covered some years ago. No eye disease nor other signs of ill he alt h was found. Several of the reports in the Company file. C03520 1- - * . alluded to above, regarding exposure of workers were discussed. The study of aerial and ground applicator exposure under field conditions by Lauer and Arras was reviewed. This study found that the total body dose computed from inhalation and dermal absorption during tank fill and application, was 13.64 yg/kg body weight/ hundred acr-e application. On this basis about 1.0 mg would be taken up by such wor ker s in the course of spraying 100 acres, w h i c h is about the amount that one worker could do in a day. The highest total body dosage per pound of Alachlor applied was 0.034 yg/kg body weight. This worked out to be 0.02 yg/kg body w e i g h t / d a y over a lifetime, w h i c h in turn computes to a lifetime risk of d e v el opi ng a tumor based on the animal studies of about 1 0 ~ 8 . This is done in accord with the EPA mode of calculation in w h i c h the ac cep tab le risk is usually put at a chance of 10-6 of d e v e l o p i n g a tumor in a lifetime. It is known that c h l o r o a c e t a n i 1ides in general are skin sen si ti zer s that result in skin rashes with/without burning and itching. In studies of skin pene tration of Alachlor in monkeys dosed w ith 12 mg per 8 c m 2 of skin, 15% of the Alachlor applied was excreted in the urine over a 5 day period with a t 1/2 of 31 hours. A p p r o x i m a t e l y 70% of parenteral doses appear in the urine, wi th smaller amounts in the stool, over a 5 day period. Urinary m e a s u r e m e n t s appear to be a good way of determining uptake of the compound by man from the environment. Wh en human cadaver skin is studied in a diffusion chamber it is found that only 1% of acet anilide crosses the barrier, but this of course is not a circ ulated organ, and may not represent the q u a n t i t a t i v e potential of normal human skin to take up the compound. It was concluded from many studies that dermal uptake is pr ob a b l y the main route for uptake of Alachlor by man. No data, however, are available on plasma and u r i nary levels of the compound in,human beings exposed to this material. It was r e c o m mended by the Committee that such studies be undertaken with sampl ing of urine at various times after exposure of workers to the compound under field conditions. The risk assessments which have been made thus far on the compound are dependent upon assumptions about air content and dermal uptake. The study of the urinary excretion of Alachlor m e t a b o l i t e s wou ld provide a better estimate of the dose taken up, which in turn would aid in refining risk assessments. The next topic discussed was the metabolism of isotopically labelled Al ach lor in rats. A large variety of metabolites have been identified which are derivatives that retain the basic ac et a n i l i d e structu re with conju g a t i o n to thiols. F o u r t e e n compou nds identified in the urine all contain substituted thiols presumably originally derived from glutathione. Some are further oxidized to sulfones. sulfoxides and sulfates. Two were gl uc ur on ic acid conjugates. Some of the compounds were degraded further to 4 - a m i n o - 3 ,5 - d i e t h y l p h e n y 1 sulfate and compounds 2- - hydroxyla ted in the two position of the ethyl side chain. In some compounds the nitrogenous side chain bearing the methoxymethy1 group is eliminat ed but in general the acetanilide structure is preserved. This bio che mi stry is discussed more completely in the information circulated to the Committee. Dr. Golberg asked how the doses for testing were selected, above 42 mg/kg (equivalent to approximately 1000 p p m ) . The dosage levels were initially set on a mg/kg basis (14. 42. 126) to be equivalent to the dietary concentration (100, 300, 1000 ppm) used in previous Industrial Biotest studies. However, as the animal gained weight and ate proportionately less treated diet, the dietary concentrations were increased nearly 3-fold to maintain the initial dosages. A d m i n i s t e r i ng compounds in the diet in terms of ppm of diet is equivalent to administering compounds in mmoles/ calorie which correlates better with surface area and energy expenditure rather than with body weight. Adjusting the dose for body weight, taking into account changes in food intake and body weight, will give a higher dose than maintaining a constant pe rc en ta ge in the diet. It is clear now that 126 mg/kg is beyond the m a x i m u m tolerated dose because of weight loss, increased m o r t a l i t y rates, and enlargement of liver and other organs. Dr. Go lb er g argued that a very important set of experiments should be done to study the d i s t r ibution and me tabolism of Alach lor at both high and low doses. It was his belief, agreed to by the Committee, that the pattern of m e t a b o l i s m might be quite di ff e r e n t at high doses as compared with low doses and -it would be important to determine the patterns under the two conditions of animal feeding. It would also be important to study the uptake of the compound and met ab olites by various organs that have been obser ved to have pathologic changes under high dose feeding, such as the thyroid, the stomach, the nasal turbinates, the lung and the brain. Since 90% of Alachlor and its metabolites are excreted in the urine and feces in 4 days it would be important to d e t e r mine the dose response curves for Alachlor administered in various ways to ani mals in pre pa ra tion for doing similar studies in man. It was recomme nde d that hepatic glutathione levels be measured under high and low dose feedings because of the high percentage of sulfur con jugates whic h have been identified so far. Dr. Go lb er g also recommended that the degree of hemoglobin and DNA d e r i v a t i z a t i o n by Al achlor or its metabolit.es be measured as an index of covalent m o d i f i c a t i o n of macr omolecule s by the c o m pound, w h ic h could bear on its action as a carcinogen. A paper by Werner K. Lutz (Banbery Series. Session IV: DNA Adducts, 189-204) from the Institute of Toxicology. Zurich, entitled Covalent B i n d ing Index - DNA Binding in Vivo as a Q u a n t itative Indicator for G e n o t o x i c i t y , which sum marizes recent advances in this area measuring carcinogenic potency by determining DNA binding was cited by Dr. Golberg. 3- - ' n 9* It was agreed that the Company scientists concerned with the study of Alachlor m e t a bolism and related issues would circulate to the Bio haz ard s Co mm itt ee within the next two weeks all the data a va il ab le on m e t a b o l i s m and exposure of workers and would prepare a draft of a pr og ra m to s y s t e maticall y study the toxicology of Ala ch lo r for d i s c u s s i o n at the next meeting of the Biohazards Co mm i t t e e w hic h will occur on September 15-16, 1983 beginning at 2:00 p.m. following the Monsanto S ymposium on New Approaches in T ox ic it y Test ing and Their A p p l i c a t i o n to Human Risk Assessment. Item two on the agenda "Uncoupling Chemicals and Cancer" was suggested by Dr. Richard Mahoney, the new President of Monsanto and Mr. Joe Nolan, Vice President for Public Relations. Could the Company carry on a campaign to educate the public about the true role of chemicals in biology and to disabuse laymen of the view that all chemicals are toxic. Since living tissues are composed of many chemicals, and the m a i n tenance of life is dependent upon chemical reactions that generate energy, which in turn is required for the performance of work by all living forms, chemicals are essential for life. Only selected chemicals can injure or alter the e x p res sio n of genes which in turn can lead to a change in the phe no ty pe of cells, so-called transformatio n of cells. It was agreed by the Com mi tte e that this is a very wo rthwhile project and that the Com pa ny should invest some money in carrying out a c am pa ig n of this kind. The q uestion is how to do it. Should this effort center about the appointment of professors in large or small insti tutio ns of higher learning, who would devote more of their time to teaching the bioc h e m i s t r y of cancer, and the role of environment. Some one should put into perspective the various risks that face human beings on this planet, including the risk of cancer. Dr. Olso n suggested that the American Council on Science and Health might be a useful vehicle for getting informa tive papers into popular and semi-popular journals. Dr. Beth W h e l a n is Exe cut ive Dir ector of this organization. The next item on the agenda was a d i s cussion of a newly di sc o v e r e d epidemic of purported h e m o g lobinuri a in workers at the Pensacola Plant. No red cells, however, were found in the sedi ment. The positive tests for hemoglobin were based on the benzi dine test. The average prevalence of positive hemaglobin tests by this me th od in the urine of C o m pany employees is about 3%, wh er e a s in Pen sac ola 400 out of 4400 people or about 8% were positive. This positive test, however, was transient and in urine standing 6 to 8 hours the chromagen disappeared. Urine spiked w it h h e m o g l o b i n will remain positive for many hours. A l t h o u g h it seems that these results are false positives, the question is what or who is re spo nsi ble? By preli m i n a r y gel filtration of the 200 mg of pr ot ei n found norma lly in a 24 hour urine, the offending material was adsorbed to a prot ein of about 60,000 molecular weight, w h i c h could be albumin. This fraction should be tested for the sp ec t r u m of h e m og lobin or hematin. If negative, the reacting substan ce should be isolated. D istribution of pos it ive urines is not segregated to one part of the factory 4- - or any one process. It is dist ributed among workers and e x e c u tives but is not present in the general population. Could it be a com pon ent of the diet served at Pensacola? The problem is under investigation. The next item was the issue of dioxin-related soft tissue sar comas presented by Dr. W i l l i a m R. Gaffey. Of the soft tissue sarcomas that have been associated with deaths of workers at Monsanto, are they related biologically? Of the five cases which we examined it was clear that the tumor in one case, that of David L. Clu ck who had wo rke d for the Company for only two years and who died at age 34 of a me ta st atic mesothelioma, could not have arisen because of occupational exposure. Of the four remaining cases two had lipo sar com as and one a fibrous histiocytoma which could be c o n si de red related. The ma lignant schwannoma which is tissue of a di ff e r e n t origin and dif ferent cell-type is clearly different. As the cell- typ e in these sarcomas varies considerably, it was Dr. Kus ch ne r' s opi ni on that three of the four might be related. The Committee requested that slides be obtained from these patients for examination by Dr. Kuschner and the Company agreed. The next item was a d i s c u s s i o n of advances in the u n d e r s t a n d ing of mali gn ant tr an sf ormation particularly as reflected by recent papers in the New England Journal of Medicine (T. G. Konteres: Emerging Genetics of Human Cancer, NEJM 3 0 9 . (August) 404. 1983) and the Lancet (P. Ha mlyn and K. Sikora: Oncogenes, Lancet II, 326, 1983). Should knowledge of oncogenes affect the att it ud e of the Comp an y toward carcinogenesis? The new concepts illu min ate the process by w hich expression of new genes occurs to change the phe not ype of normal tissue to tumor. It should lend support to con ti nu in g studies of DNA modi f i c a t i o n by compounds of interest to the Company, such as suggested today for Alachlor. The sixth item was a report by an a_d hoc working group on oil gavage in tox ic ol og y sporsored by the Nutrition Foundation. It was a review of current li terature by an expert Committee chaired by Dr. Jel li f f e Carr of Columbia, Maryland and composed of a number of toxicologists known to the Committee. They concluded that corn oil gavage may not be the best vehicle for administering ca rc ino gen s to rats because of several features. Corn oil: 1) may change the distribution of the compound between oil and other fluids of the gastrointestinal tract which may promote absorption of compou nds no rma lly deg raded by digestive enzymes; 2) may increase peak loads in the blood; 3) adds calories to the intake of the exp er im ent al animal; and 4) is not to be recommended for NCI type long-term carcinogenesis studies. The sev ent h item on the agenda was a consideration of a request from the Rene Dubos F o u n d a t i o n in New York for funds to support symposia wh ich permit interaction of industry scientists, and consumer advocates. The Committee viewed this project with some s k e pti cis m since there has been no program set forward and no topics defined. Bec ause of the vagueness of the proposal and 5- - the lack of defi ni ti on the Committee recommended that the Company not support this proposal. Jim Wilson touched on two points. He wanted the Committee's op in i o n on a press w ork shop to try to improve the understanding of the working press about the Company's attitude toward carcino genesis and their attempts to institute good occupational health practices and a good toxicology program. The Committee supported that. The other proposal was that Dr. Alan Poland, a biochemist at the McC ar d l e Institute for Cancer Research, University of W i s c o ns in- Ma di son . be invited to come to Mons anto and talk about his studies on receptors for dioxins. The Committee, all of whom know A l a n Poland, agreed that he is an excellent speaker and recommended that he be invited to present a seminar at Monsanto at some future meeting of the Biohazards Committee. The meet ing was adjourned at 3:00 p.m. The next meeting will occur on S e p t e m b e r 15-16, 1983. "I Robert E.` Olson, M.D. Secretary, Monsanto Biohazards Committee 6- -