Comparative Results of 327 Chemical Carcinogenicity Studies

Haseman, J. K.; Huff, James; Zeiger, Errol; McConnell, Ernest E.

doi:10.2307/3430453

Cited by 40 publications

(28 citation statements)

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“…The carcinogenic status of a chemical can therefore only be determined by reference to lifetime carcinogenicity bioassay data (2,44). Even so, it must be noted that the carcinogenic status of a chemical is not itself an absolute entity, as seen for TMTU in the present study in comparison to the NTP bioassay, and as noted for a range of other chemicals evaluated in accelerated transgenic rodent bioassays (5)(6)(7)45).…”

Section: Discussionmentioning

confidence: 79%

“…To this end, we simulated as far as possible the conditions of bioassay used by the NTP while defining the carcinogenicity of nine rodent carcinogens (44). During the early stages of this simulation, we evaluated a range of acute/subacute markers of presumed nongenotoxic rodent carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Carcinogenic status as described in the NTP reports: CE, clear evidence for carcinogenicity; NE, no evidence for carcinogenicity. Carcinogenic status as described by Haseman et al (44): N,negative for carcinogenicity; P,positive for carcinogenicity. Tumor data were summarized from the NTP Technical Reports cited; only the tumor data that led to the classification of the compound as carcinogenic are displayed.…”

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confidence: 99%

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Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

Elcombe

Odum

Foster

et al. 2002

Environ Health Perspect

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We studied nine presumed nongenotoxic rodent carcinogens, as defined by the U.S. National Toxicology Program (NTP), to determine their ability to induce acute or subacute biochemical and tissue changes that may act as useful predictors of nongenotoxic rodent carcinogenesis. The chemicals selected included six liver carcinogens (two of which are peroxisome proliferators), three thyroid gland carcinogens, and four kidney carcinogens. We administered the chemicals (diethylhexyl phthalate, cinnamyl anthranilate, chlorendic acid, 1,4-dichlorobenzene, monuron, ethylene thiourea, diethyl thiourea, trimethyl thiourea, and d-limonene to the same strains of mice and rats used in the original NTP bioassays (nine chemicals to rats and seven to mice). Selected tissues (liver, thyroid gland, and kidney) were collected from groups of animals at 7, 28, and 90 days for evaluation. Tissue changes selected for study were monitored for all of the test groups, irrespective of the specificity of the carcinogenic responses observed in those tissues. This allowed us to assess both the carcinogen specificity and the carcinogen sensitivity of the events being monitored. We studied relative weight, cell labeling indices, and pathologic changes such as hypertrophy in all tissues; a range of cytochrome P450 enzymes and palmitoyl coenzyme A oxidase in the liver; changes in the levels of plasma total triiodothyronine, total thyroxine, and thyroid-stimulating hormone (TSH) as markers of thyroid gland function; and hyaline droplet formation, tubular basophilia, and the formation of granular casts in the kidney. There were no single measurements that alerted specifically to the carcinogenicity of the agents to the rodent liver, thyroid gland, or kidney. However, in the majority of cases, the chemical induction of cancer in a tissue was preceded by a range of biochemical/morphologic changes, most of which were moderately specific for a carcinogenic outcome, and some of which were highly specific for it (e.g., increases in TSH in the thyroid gland and increases in relative liver weight in the mouse). The only measurements that failed to correlate usefully with carcinogenicity were the induction of liver enzymes (with the exception of the enzymes associated with peroxisome proliferation). Most of the useful markers were evident at the early times studied (7 days and 28 days), but no overall best time for the measurement of all markers was identified. The judicious choice of markers and evaluation times can aid the detection of potential nongenotoxic rodent carcinogens.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

Elcombe

Odum

Foster

et al. 2002

Environ Health Perspect

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“…Approximately 60% of the chemicals determined by the National Toxicology Program to be carcinogenic in rats and mice give rise to liver tumors (Haseman et al, 1987). We have postulated that the carcinogenic eect of at least some of these compounds results from their ability to release hepatocytes from normal hepatic growth controls (Jirtle et al, 1994;Mills et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Imprinted M6p/Igf2 receptor is mutated in rat liver tumors

et al. 1998

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We have previously shown that inactivation of mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/ IGF2R) is a common early event in both human liver and breast carcinogenesis. The M6p/Igf2r is imprinted in mice while expression is biallelic in most humans. In this investigation the M6p/Igf2r gene is shown to also be imprinted in the liver of Fischer 344, Lewis and Brown Norway rats. In addition, we have identi®ed mutations in the expressed allele of the M6p/Igf2r in 40% of diethylnitrosamine-initiated rat liver tumors. These results provide further evidence that the M6P/IGF2R functions as a liver tumor suppressor gene. They also suggest that mice and rats would be more sensitive than humans to those hepatocarcinogens in which the M6p/ Igf2r is mechanistically involved in transformation since one rather than two alleles would need to be inactivated.

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“…More animals are used, both sexes of two species are exposed, generally higher doses are administered, and the effects at several dose levels (usually at least three) are included (5). Of 266 chemicals considered to have been adequately tested in rats and mice of both sexes at or near the MTD in 2-year protocols by the National Toxicology Program (NTP) and the National Cancer Institute (NCI), 51% percent were found to be positive for carcinogenicity in at least one sex-species group; the evaluation of positivity was according to the conclusions stated in the NCI/NTP Technical Reports (6,7).…”

Section: Which Chemicals Are Carcinogens?mentioning

confidence: 99%

Predicting the Carcinogenicity of Chemicals in Humans from Rodent Bioassay Data

Goodman¹,

Wilson²

1991

Environmental Health Perspectives

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Regulatory agencies currently rely on rodent carcinogenicity bioassay data to predict whether or not a given chemical poses a carcinogenic threat to humans. We argue that it is always more useful to know a chemical's carcinogenic potency (with confidence limits) than to be able to say only qualitatively that it has been found to be a carcinogen. In a typical bioassay, a chemical is administered to groups of 50 to 100 rodents at the highest feasible level (the maximum tolerated dose) and rarely at less than 1/10 this dose in order to maximize the statistical significance ofany increase in tumors that might result. Recently, much experimental work has focused on the mechani by which site-specific toxicity arising from chronic administration at the maximum tolerated dose may lead to carcinogencity. Extrapolation ofhigh-dose results to low doses does not take into consideration the possibility ofa threshold dose, below which the carcuiogenic potency is much lower or even zero. Threshold dose-response phenomena may be much more relevant to the etiology of cancer in the rodent bioassays than was earlier realized; if so, there is an even greater need for establishing dose-dependent potency estimates. The emphasis of this review is on the interspecies comparison of high-dose potencies. The qualitative and quantitative comparison ofcarcinogenicities between mice and rts and between rodents and humans isreviewed and discussed.We conclude that there is a good qualitative (yes/no) correlation for both the rat/mouse and the rodent/human comparison. There is also a good correlation of the carcinogenic potencies between rats and mice, and the upper limits on potencies in humans are consistent with rodent potencies for those chemicals for which human exposure data are available. For the rodent/human comparison, the best estimate ofthe interspecies potency factor is lognormally distributed around 1 when the potencies in both species are measured in units of (mg/kg-day) -'.

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Comparative Results of 327 Chemical Carcinogenicity Studies

Cited by 40 publications

References 4 publications

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

Imprinted M6p/Igf2 receptor is mutated in rat liver tumors

Predicting the Carcinogenicity of Chemicals in Humans from Rodent Bioassay Data

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