- Email: [email protected]
Assessment of carcinogenic hazard of pesticides
92
Poster Session 2A. Biotransformation, Metabolism
on average animal weight. These corrected numbers of tumors are then used to test the statistical significance of the observed responses and for chemical classification . The correla tion between different tumor types was calculated using odds ratio methodology. Anticarcinogenicity observed in rodent cancer bioassays should be carefully considered in evaluations of the overall carcinogenic potential of chemical s for risk assessment and regulatory purposes.
IP1 H2181
of carcinogen esis in animals may operate in human s only in part (low activity of enzymes realizing the development of tumours ): in this case the agent may be downgraded from subclass 2A or 2B to subclass 2C with the respective change in risk assessment. Downgraded also is the agent producin g tumours only at maximum tolerated dose.
IP1 H220 I METHODOLOGY OF PESTICIDE RISK ASSESSMENT ENHANCED SYSTEMIC TISSUEDISTRIBUTION AFTERTOPICALVERSUSINTRAVENOUS TCB (3,3', 4,4'-TETRACHLOROBIPHENYL) ADMINISTERED AT EQUIVALENT DOSES:A CLEAR EXAMPLEOF ROUTE DEPENDENCY IN RISK ASSESSMENT
G.L. Qiao *, J.E . Riviere. Cutaneous Pharmacol. & Toxicol. CTR, North Carolina State University, Raleigh, NC, USA As a dioxin-like PCB, 3,3', 4,4'-tetrachlorobiphenyl (TCB) commands increasing research and regulatory interest. In comparative toxicology studies, we often assume that the greater the blood AUC, the greater the systemic risk and the body burden regardless of exposure route. To examine exposure route impact on tissue disposition and related systemic health risk, 14C-TCB was administered at an identical dose of 300 f.Lg via either intravenous (IV) or topical route to swine. After IV and dermal exposure , blood , urine and feces samples were collected during the II-day studies. At the end of experiments, mass balance studie s were conducted to characterize tissue 14C disttibu tion. Exposure route effect on blood and tissue disposition of 14C was then explored. T II2 in blood was 4-5 days with 3.3X higher 14C concentr ations in blood cells than in plasma Urinary and fecal excretion was 16 and 44 % following IV dose, respectivel y, which is 10 times larger than the dermal values. However, the II-day tissue residue for IV (8%) is less than a half of that for dermal (18%). As expected, much higher blood concentrations, greater blood AUC, urine and fecal excretion were determ ined after IV than dermal . However, we unexpectedly found that the tissue concentrations in almo st all tissues were much higher with dermal than IV. This suggests an route-dependent blood/tissue partition process likely due to cutaneous metabolism, saturable hepatic biotransformation, and/or slow rate-limiting transport of labeled toxican t(s) from blood into tissues. Th is finding also confirmed that long-term dermal expo sure with a low systemic input rate of TCB could be more harmful in terms of tissue toxicity. Thus blood exposure (e.g., Cmax and AUC) is not the sole critical issue for systemic/tissue risk assessment. One mus t be aware that greater absorption, higher blood concentrations, and greater blood AUC do not necessarily equate to a greater tissue expo sure. Exposure-route-specific metaboli sm and tissue distribution must be taken into consideration in risk assessment. (Supported by US-EPA CR-824007).
IP1 H2191 ASSESSMENT OF CARCINOGENIC HAZARDOF PESTICIDES
V.S. Turusov *, A. I. Potapov, V.N. Rakitsky. Blokhin Cancer
Research Center/Erisman Institute ofHygiene, Moscow, Russian Federation, Russia Hygienic classification of pesticides adopted in Russian Federation subdivides them into four classes according to their carcinogenic hazard to humans : extremely hazardou s, hazardou s moderately and slightly hazardous. The 2nd of these classes is subdivided into 3 subclasses : 2A, 2B & 2C the latter being the least hazard ous. If the mechani sm of carcinogenesis in animals does not operate at all in human the agent can be transferred from class 2 to class 3, for example peroxysome proliferators, in case it is proven that the agent does not produce peroxisome proliferation in cultured human hepatocyte s. Mechani sm
FOR HUMANS
A.I. Potapov *, V.N. Rakitsky, L.P. Tereshkova. Erisman Institute of
Hygiene, Moscow, Russian Federation, Russia Pesticide risk assessment for operators and population at the stage of registration testing determine s the possibility of pesticide use. Concept of differentiated assessment of a potential and real pesticide hazard is used (Y.N. Rakitsky, 1997). Different types of a real pesticide hazard exist: the possibility of letal and non-letal poisoning, specific and remote effects after single or repeated application, deterioration of the environment. Real pesticide hazard is determined by the ratio between pesticide level to which operators and population can be expo sed under real conditions and the degree of the compensatory mechani sm disturbances produced by pesticides in laboratory animals (mean and minimum Ictal, threshold, non-effective levels), in the environment (threshold and non-effective levels) and in the hygienic standards on human skin, working zone and atmospheric air, water, food taking into account acceptable daily dose.
IP1 H221 I GENOTOXICITY AND NON-GENOTOXICITY OF CHEMICAL CARCINOGENS
Y.N. Rakitsky *, A.I. Potapov, Y.A. Revasova, V.S. Turusov.
Erisman Institute ofHygiene/lnstitute of Human Ecology and Environment, Moscow, Russian Federation, Russia There exist carcinogens with a high positivity in all or almost tests for genotoxicity (genotoxic carcinogens). Other carcinogens are known which produce tumours in animals but which give negative results in all tests for genotoxicity (non-genotoxic carcinogens). The carcinogens of the intermediate group are positive in some tests and negative in the others. They may be positive only in in vitro tests and few tests in vivo and can be called paragenotoxic. The risk assessment of clearly genotoxic carcinogens is made by non-threshold linear model while the risk of non-genotoxic carcinogen s is assessed by means of NOEL (no observable effect level), thus by recognition of threshold. The distinction of the third (intermediate) group may, in our opinion, make risk assessment and reglamentation more differentiated. The examples of carcinogens from each group will be given.
P2A. Biotransformations, Metabolism
IP2A1 I
INDUCTION OF HEPATIC P450BY PENTOBARBITAL IN SEMI-AQUATIC FROG(RANA PIPIENS)
S.Y. Qadri , M.A.Q. Khan *. Biological Sciences, University of Illinois, Chicago, USA Hepatic microsomal cytochrome P450 was induced by pentobarbital (PB) only in adults of Ranapipiens and not of Xenopuslaevis (aquatic frog) and Lepomis macrochirus (bluegill sunfish). The activity of PB-induced P4502B toward aldrin, chlordene, and pento xyresorufin increased by 2-, 3-, and Io-fold, respectively. However, P450lAI was induced in larval, post-larval, and adult stages of both frogs and in bluegills. The total P450 concentration increased slightly during the post-larval stages of Rana until the adult stage was reached. Th is increase was mostly due to P4502B isoform as judged by the
Poster Session 2A. Biotransformation, Metabolism
on average animal weight. These corrected numbers of tumors are then used to test the statistical significance of the observed responses and for chemical classification . The correla tion between different tumor types was calculated using odds ratio methodology. Anticarcinogenicity observed in rodent cancer bioassays should be carefully considered in evaluations of the overall carcinogenic potential of chemical s for risk assessment and regulatory purposes.
IP1 H2181
of carcinogen esis in animals may operate in human s only in part (low activity of enzymes realizing the development of tumours ): in this case the agent may be downgraded from subclass 2A or 2B to subclass 2C with the respective change in risk assessment. Downgraded also is the agent producin g tumours only at maximum tolerated dose.
IP1 H220 I METHODOLOGY OF PESTICIDE RISK ASSESSMENT ENHANCED SYSTEMIC TISSUEDISTRIBUTION AFTERTOPICALVERSUSINTRAVENOUS TCB (3,3', 4,4'-TETRACHLOROBIPHENYL) ADMINISTERED AT EQUIVALENT DOSES:A CLEAR EXAMPLEOF ROUTE DEPENDENCY IN RISK ASSESSMENT
G.L. Qiao *, J.E . Riviere. Cutaneous Pharmacol. & Toxicol. CTR, North Carolina State University, Raleigh, NC, USA As a dioxin-like PCB, 3,3', 4,4'-tetrachlorobiphenyl (TCB) commands increasing research and regulatory interest. In comparative toxicology studies, we often assume that the greater the blood AUC, the greater the systemic risk and the body burden regardless of exposure route. To examine exposure route impact on tissue disposition and related systemic health risk, 14C-TCB was administered at an identical dose of 300 f.Lg via either intravenous (IV) or topical route to swine. After IV and dermal exposure , blood , urine and feces samples were collected during the II-day studies. At the end of experiments, mass balance studie s were conducted to characterize tissue 14C disttibu tion. Exposure route effect on blood and tissue disposition of 14C was then explored. T II2 in blood was 4-5 days with 3.3X higher 14C concentr ations in blood cells than in plasma Urinary and fecal excretion was 16 and 44 % following IV dose, respectivel y, which is 10 times larger than the dermal values. However, the II-day tissue residue for IV (8%) is less than a half of that for dermal (18%). As expected, much higher blood concentrations, greater blood AUC, urine and fecal excretion were determ ined after IV than dermal . However, we unexpectedly found that the tissue concentrations in almo st all tissues were much higher with dermal than IV. This suggests an route-dependent blood/tissue partition process likely due to cutaneous metabolism, saturable hepatic biotransformation, and/or slow rate-limiting transport of labeled toxican t(s) from blood into tissues. Th is finding also confirmed that long-term dermal expo sure with a low systemic input rate of TCB could be more harmful in terms of tissue toxicity. Thus blood exposure (e.g., Cmax and AUC) is not the sole critical issue for systemic/tissue risk assessment. One mus t be aware that greater absorption, higher blood concentrations, and greater blood AUC do not necessarily equate to a greater tissue expo sure. Exposure-route-specific metaboli sm and tissue distribution must be taken into consideration in risk assessment. (Supported by US-EPA CR-824007).
IP1 H2191 ASSESSMENT OF CARCINOGENIC HAZARDOF PESTICIDES
V.S. Turusov *, A. I. Potapov, V.N. Rakitsky. Blokhin Cancer
Research Center/Erisman Institute ofHygiene, Moscow, Russian Federation, Russia Hygienic classification of pesticides adopted in Russian Federation subdivides them into four classes according to their carcinogenic hazard to humans : extremely hazardou s, hazardou s moderately and slightly hazardous. The 2nd of these classes is subdivided into 3 subclasses : 2A, 2B & 2C the latter being the least hazard ous. If the mechani sm of carcinogenesis in animals does not operate at all in human the agent can be transferred from class 2 to class 3, for example peroxysome proliferators, in case it is proven that the agent does not produce peroxisome proliferation in cultured human hepatocyte s. Mechani sm
FOR HUMANS
A.I. Potapov *, V.N. Rakitsky, L.P. Tereshkova. Erisman Institute of
Hygiene, Moscow, Russian Federation, Russia Pesticide risk assessment for operators and population at the stage of registration testing determine s the possibility of pesticide use. Concept of differentiated assessment of a potential and real pesticide hazard is used (Y.N. Rakitsky, 1997). Different types of a real pesticide hazard exist: the possibility of letal and non-letal poisoning, specific and remote effects after single or repeated application, deterioration of the environment. Real pesticide hazard is determined by the ratio between pesticide level to which operators and population can be expo sed under real conditions and the degree of the compensatory mechani sm disturbances produced by pesticides in laboratory animals (mean and minimum Ictal, threshold, non-effective levels), in the environment (threshold and non-effective levels) and in the hygienic standards on human skin, working zone and atmospheric air, water, food taking into account acceptable daily dose.
IP1 H221 I GENOTOXICITY AND NON-GENOTOXICITY OF CHEMICAL CARCINOGENS
Y.N. Rakitsky *, A.I. Potapov, Y.A. Revasova, V.S. Turusov.
Erisman Institute ofHygiene/lnstitute of Human Ecology and Environment, Moscow, Russian Federation, Russia There exist carcinogens with a high positivity in all or almost tests for genotoxicity (genotoxic carcinogens). Other carcinogens are known which produce tumours in animals but which give negative results in all tests for genotoxicity (non-genotoxic carcinogens). The carcinogens of the intermediate group are positive in some tests and negative in the others. They may be positive only in in vitro tests and few tests in vivo and can be called paragenotoxic. The risk assessment of clearly genotoxic carcinogens is made by non-threshold linear model while the risk of non-genotoxic carcinogen s is assessed by means of NOEL (no observable effect level), thus by recognition of threshold. The distinction of the third (intermediate) group may, in our opinion, make risk assessment and reglamentation more differentiated. The examples of carcinogens from each group will be given.
P2A. Biotransformations, Metabolism
IP2A1 I
INDUCTION OF HEPATIC P450BY PENTOBARBITAL IN SEMI-AQUATIC FROG(RANA PIPIENS)
S.Y. Qadri , M.A.Q. Khan *. Biological Sciences, University of Illinois, Chicago, USA Hepatic microsomal cytochrome P450 was induced by pentobarbital (PB) only in adults of Ranapipiens and not of Xenopuslaevis (aquatic frog) and Lepomis macrochirus (bluegill sunfish). The activity of PB-induced P4502B toward aldrin, chlordene, and pento xyresorufin increased by 2-, 3-, and Io-fold, respectively. However, P450lAI was induced in larval, post-larval, and adult stages of both frogs and in bluegills. The total P450 concentration increased slightly during the post-larval stages of Rana until the adult stage was reached. Th is increase was mostly due to P4502B isoform as judged by the