U.S. Environmental Protection Agency guidelines for carcinogen risk assessment: Past and future

Wiltse, Jeanette; Dellarco, Vicki L.

doi:10.1016/s0165-1110(96)90009-3

Cited by 42 publications

(23 citation statements)

References 21 publications

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“…In evaluating the carcinogenic potential of a compound, it is important to consider the route of exposure because the hazard and risk posed by a compound may vary by exposure route (37). Delivery of the reactive intermediate to target macromolecules such as DNA is crucial for carcinogenic activity, and exposure routes such as inhalation and injection are often required for maximal activity for direct-acting reactive chemicals.…”

Section: Conditions Of Hazard Expression (Routes Of Exposure)mentioning

confidence: 99%

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

Woo

Lai

McLain

et al. 2002

Environ Health Perspect

224

100

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Disinfection by-products (DBPs) are formed when disinfectants such as chlorine, chloramine, and ozone react with organic and inorganic matter in water. The observations that some DBPs such as trihalomethanes (THMs), di-/trichloroacetic acids, and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) are carcinogenic in animal studies have raised public concern over the possible adverse health effects of DBPs. To date, several hundred DBPs have been identified. To prioritize research efforts, an in-depth, mechanism-based structure-activity relationship analysis, supplemented by extensive literature search for genotoxicity and other data, was conducted for ranking the carcinogenic potential of DBPs that met the following criteria: a) detected in actual drinking water samples, b) have insufficient cancer bioassay data for risk assessment, and c) have structural features/alerts or short-term predictive assays indicative of carcinogenic potential. A semiquantitative concern rating scale of low, marginal, low-moderate, moderate, high-moderate, and high was used along with delineation of scientific rationale. Of the 209 DBPs analyzed, 20 were of priority concern with a moderate or high-moderate rating. Of these, four were structural analogs of MX and five were haloalkanes that presumably will be controlled by existing and future THM regulations. The other eleven DBPs, which included halonitriles (6), haloketones (2), haloaldehyde (1), halonitroalkane (1), and dialdehyde (1), are suitable priority candidates for future carcinogenicity testing and/or mechanistic studies.

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Section: Conditions Of Hazard Expression (Routes Of Exposure)mentioning

confidence: 99%

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

Woo

Lai

McLain

et al. 2002

Environ Health Perspect

224

100

View full text Add to dashboard Cite

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“…Carcinogens are now generally recognized as exerting their carcinogenicity either through entirely epigenetic effects involving no interaction of the carcinogen with DNA or through DNA-reactive (genotoxic) effects, which may be accompanied by epigenetic effects Whysner, 1995,1996;Wiltse and Dellarco, 1996;Williams et al, 2000). Epigenetic carcinogens typically require high-level exposure to produce the cellular effect underlying their enhancement of tumor development.…”

Section: Introductionmentioning

confidence: 99%

“…This is a true toxicologic threshold in the same sense as physiologic or pharmacologic thresholds. For such epigenetic agents, regulatory agencies will allow a margin of exposure (MOE) risk assessment (Wiltse and Dellarco, 1996;Page et al, 1997), which implies a threshold or acceptable risk.…”

Section: Introductionmentioning

confidence: 99%

Thresholds for the Effects of 2-Acetylaminofluorene in Rat Liver

2004

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To explore for practical thresholds for DNA-reactive carcinogens in rat liver carcinogenicity, we have conducted a series of exposure-response studies using 2 well-studied hepatocarcinogens, 2-acetylaminofluorene (AAF) and diethylnitrosamine (DEN). Findings with AAF, including as yet unpublished experiments, are reviewed here and related to DEN observations. In these studies, we have administered exact intragastric doses during an initiation segment (IS) of 12-16 weeks followed in some experiments by phenobarbital (PB) as a liver tumor promoter for 24 weeks to enhance manifestation of initiation. The cumulative doses (CD) of AAF at the end of ISs ranged from 0.094 to 282.2 mg/kg. Our findings for AAF in the IS can be summarized as follows: (1) the earliest parameter to be affected with administration of low doses was the appearance of DNA adducts (around 4 weeks), followed at higher doses by cell proliferation; (2) formation of DNA adducts was nonlinear, with a no-observed effect level (NOEL) at a CD of 0.094 mg/kg and a plateau at higher doses (94.1 mg/kg); (3) cytotoxicity (necrosis) showed a NOEL at a CD of 28.2 mg/kg; (4) compensatory hepatocellular proliferation showed a NOEL at a CD of 28.2 mg/kg and was supralinear at a high CD (282.2 mg/kg); (5) formation of preneoplastic hepatocellular altered foci (HAF) showed a NOEL at a CD of 28.2 mg/kg, and was supralinear at a high CD (282.2 mg/kg); (6) a NOEL (CD 28.2 mg/kg) was found for tumor development and the exposure-response was supralinear. We interpret these findings to reflect practical thresholds for hepatocellular initiating effects of AAF and exaggerated responses at high-exposures doses, as also found for DEN. Thus, mechanisms of carcinogenesis can differ between low and high doses.

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“…For agents with these characteristics that are also nongenotoxic, regulatory agencies will allow use of a margin of exposure in risk assessment (25,57). Implicit in such an approach is the idea that carcinogens of this type have thresholds.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Basis for Nonlinearities and Thresholds in Rat Liver Carcinogenesis by the DNA-Reactive Carcinogens 2-Acetylaminofluorene and Diethylnitrosamine

2000

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To explore differences in mechanisms of carcinogenicity at low and high exposures, we have conducted a series of exposureresponse studies of hepatocarcinogenesis in rats using 2 well-studied DNA-reactive carcinogens, 2-acetylaminofluorene and diethylnitrosamine. In these studies, we have used intraperitoneal injection or intragastric instillation to deliver exact doses during an initiation segment followed by phenobarbital as a liver tumor promoter to enhance manifestation of initiation. This protocol results in carcinogenicity comparable to that produced by lifetime exposure to the carcinogens. Our

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U.S. Environmental Protection Agency guidelines for carcinogen risk assessment: Past and future

Cited by 42 publications

References 21 publications

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

Thresholds for the Effects of 2-Acetylaminofluorene in Rat Liver

Mechanistic Basis for Nonlinearities and Thresholds in Rat Liver Carcinogenesis by the DNA-Reactive Carcinogens 2-Acetylaminofluorene and Diethylnitrosamine

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