Document G64vewG7ze86B1Q99Ln3zYZ87

.Mil Dept, of Medicine & Environmental Health - P ,L. Wright, G2WF DATE February 3, 1981 cc, G.J. Levinskas, G2WF ' SUBJECT Tumorigenicity of Hexachlorodibenzo-p-dioxin (HCDD) TO G. Roush, Jr., M.D., ,G2WG The Nati,onal Cancer Institute has i.ssued two reports'( 1 '2 )' on the tumorigenicity of HCDD following oral (gavage) *or dermal admini stration. A mixture of 1,2,3,6 ,7,8 HCDD and 1,2,3,7,8,9 HCDD when administered to male and female rats and male mice at doses up to 5 pg/kg/week and to female mice at doses up to 10 pg/kg/week resulted in statistically significant increases in hepatocellular adenomas in male and female mice and hepatic neoplastic nodules in female rats. Male rats were not affected. The incidence of hepato cellular carcinoma was variable but was not statistically signi ficantly increased in any group. The incidence of other neoplastic lesions did not differ among control and treated animals. In a previ,ous study, Koci,ba'( 3 \ 7 reported an .increased i, ncidence of hepatocellular carcinomas and squamous cell carcinomas of the lung in rats fed diets providing 0.1 pg 2,3,7,8 tetrachlorodibenzo- p-dioxin (TCDD) per day. Rats given 0.01 pg/kg/day had increased liver (hepatocellular nodules) and lung (focal-alveolar hyperplasia) lesions. The HCDD used in the NCI study contained approximately 0.1 ppm TCDD and 0.4 to 1.4 ppm pentachlorodibenzo-p-dioxin (PCDD). These are assumed to have been predominantly 2 ,3,7,8 containing isomers. Thus, it is.possible that the animals in the NCI study could have been exposed to 0.005 pg TCDD/week and 0.02 to 0.07 pg PCDD/week. These levels approach the tumorigenic levels of TCDD in the Dow study. The relative tumorigenicity of PCDD has not been reported making it impossible to directly evaluate the effects of the TCDD and PCDD contamination in the HCDD used in the NCI study. A 90-day rat feeding, study'/A\7 with pentachlorophenol containing 19 ppm HCDD has been reported. -In that study,* increased liver weights were observed at pentachlorophenol dosages as low as SUBJECT TO PROTECTIVE ORDER. 1 Technical Report Series No. 198, NTP No. 80-12 (1980). 2 Technical Report Series No. 202, NTP No. 80-13 (1980). 3 Kociba, et al (Dow) TAP 46:279-303 (1978). 4 Johnson, et al (Dow) Envir. Health Perspec., Sept., 1973, pp. 171-175. C 03085 1N-1QM ( R E V . 2/78) G. Roush, Jr., M.D., G2WG February 3, 1981 Page -2- 3 mg/kg/day and microscopic liver lesions were seen at 30 mg/kg/day. With chemically pure pentachlorophenol, liver weight increases were observed at 10 mg/kg/day, but no microscopic lesions were foynd even at 30 mg/kg/day. The commercial pentachloro sample tested^ } would have contributed a calculated 0.057 fig HCDD/kg/day or approximately 0.4 fig/kg/week in a pentachlorophenol dosage that induced evidence of toxicity after 90 days. This dosage is well below the lowest level (1.25 fig/kg/week) of HCDD that increased the incidence of neoplastic nodules in female rats; male rats were not affected at dosages as high as 5 |jg HCDD/kg/week. An important difference exists between the HCDD isomer composition of the NCI test material and the HCDD composition anticipated from our pentachlorophenol production conditions. The isomers pre sent in the NCI test material were both chlorinated in the 2,3,7,8 positions. Chlorination in these positions produces the most toxic dioxin isomers. An industry composite pentachlorophenol sample, believed to be representative of Monsanto pentachlorophenol, has been analyzed and found to contain less than 10 ppm HCDD. The HCDD isomer composition in pentachlorophenol (see attached,, J. Wilson to P. Wright, 1/20/80) would be expected, on a statistical basis, to contain only 12.5% of ah isomer chlorinated in the 2,3,7,8 positions. It is unlikely that any significant risk of liver tumor induction due to HCDD contamination in pentachlorophenol exists. To approach an exposure to HCDD from pentachlorophenol equivalent to that pro ducing tumors in the NCI study, would result in early indications of other toxic manifestations resulting from pentachlorophenol expo sure . alw attachment Paul L. Wright from (NAME--LOCATItt.n- phone.) 0. D. Wilson - N3A - 4-5274 ;*TE ! January 20, T980 SUBJECT : Hexachlorodibenzodioxins in Pentachlorophenol REFERENCE : T O :: P. L. Wright - G2WF cc. p . J. Arnall - B3NJ c. F. Cal U s - B3CA H. W. Kilbourne - N3A D. P. Roman - N3B Attached is a copy o f an a n a ly sis of an industry-com posite pentachlorophenol sample. I t is believed to be representative of Monsanto's pentachlorophenol, at le a st that produced after about 1960. Regarding your question on hexachlorodibenzodioxin isomer analyses: as fa r as I know, no such work has been done. I am not sure that anyone in the world has demonstrated the c a p a b ility to do this. As fa r as I know, o n ly the two-isomer mixture tested by NCI has been iso la te d and id e n tifie d . I f the hexachlorodibenzodioxins in "penta" are formed by condensation o f the predominant tetrachlorophenol ( 2 ,3 ,4 ,6-TeCP), and i f they are formed in s t a t is t ic a l amounts, we would expect to find s ix (of the twelve possible) isomers, in this d istrib u tion : 1.2.3.6.7.9 - 25% 1.2.3.6.8.9 - 25% 1 ,2,3,6, 7,8 -12.5% 1,2,3,6,8,9 - 12.5% 1,2,4,6,7,9 - 12.5% 1 ,2 ,4 ,6 ,8,9 - 12.5% The NCI mixture was formed bycondensation of the tetrachlorophenol isomer (2,3,4,5 - TeCP) not normally present in penta. . D. Wilson /dh in - lO I REV. 8/77 l i  F a l * C I ro . . 0. Micks - 12F February 3, 1978 Pentachlorophenol - Producers Composite CC R. G. Kaley. P. R. Michael J. P. Mi eure D. P. Roman - N2B y,JL^ a / > H S Analysis of the most recent producers composite of Penta (M3-456) has been completed. The data are comparable to previous composites and are listed below. Octachlorodibenzo-p-dioxin 1410 ppm Heptachlorodibenzo-p-dioxin 55 Hexachlorodibenzo-p-dioxin . 9.4 Pentachlorodibenzo-p-dioxin 0.03 Tetrachlorodibenzo-p-dioxin n.d. <0.01 Tricnlorodibenzo-p-dioxin n.d. <0.01 * Octachlorodibenzofuran Heptachlorodibenzofuran Hexachlorodibenzofuran Pentachlorodi benzofuran Tetrachlorodibenzofuran Trichlorodibenzofuran 182 116 6.8 1.1 0.7 . 0.02 Pentachlorobenzene Hexachlorobenzene ' 125 30 PCB's (total) n.d. <1 .0. Hicks / sf Monsanto Monsanto Company 600 N. Lindbergh Boulevard St. Louis, Missouri 63166 Phone: (314) 694-1000 February 6, 1981 TO: BIOHAZARDS COMMITTEE Drs. L. Golberg M . Kuschner R. Olson .department or medicine a environmental health Enclosed is some additional information relative to the dioxin and furan content in pentachlorophenol. During our last meeting we reviewed the NCI reports of the tumorigenicity of hexachlorodibenzo-p-dioxin. I have included the summaries from these studies. At the February 19 meeting, we would like your recommendations on the following issues: V 1) What possible health risks may have resulted from occupational exposure to pentachlorophenol. What future follow up programs should be undertaken to responsibly monitor future developments among this population. 2) What is your assessment of Monsanto's future liability for cancer development among this population. 3) Are additional studies warranted, e.g., the charac terization of the HCDD isomer distribution pentachloro phenol? We shall look forward to your discussion of this matter. Sincerely, PLW:alw c c : Dr. G. Roush, Jr. Dr. G.J. Levinskas enclosure / -;v Paul 'L. Wright, PhD