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Conflicting views on chemical carcinogenesis arising from the design and evaluation of rodent carcinogenicity studies.

Melnick RL, Thayer KA, Bucher JR - Environ. Health Perspect. (2008)

Bottom Line: Underlying these uncertainties are issues related to how experiments are designed, how rigorously hypotheses are tested, and to what extent assertions extend beyond actual findings.Issues of experimental design and evaluation that might contribute to disparate results are addressed in this article.To serve as reliable sources of data for the evaluation of the carcinogenic potential of environmental agents, experimental studies must include a) animal models that are sensitive to the end points under investigation; b) detailed characterization of the agent and the administered doses; c) challenging doses and durations of exposure (at least 2 years for rats and mice); d) sufficient numbers of animals per dose group to be capable of detecting a true effect; e) multiple dose groups to allow characterization of dose-response relationships, f) complete and peer-reviewed histopathologic evaluations; and g) pairwise comparisons and analyses of trends based on survival-adjusted tumor incidence.

View Article: PubMed Central - PubMed

Affiliation: National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA. melnickr@niehs.nih.gov

ABSTRACT
Conflicting views have been expressed frequently on assessments of human cancer risk of environmental agents based on animal carcinogenicity data; this is primarily because of uncertainties associated with extrapolations of toxicologic findings from studies in experimental animals to human circumstances. Underlying these uncertainties are issues related to how experiments are designed, how rigorously hypotheses are tested, and to what extent assertions extend beyond actual findings. National and international health agencies regard carcinogenicity findings in well-conducted experimental animal studies as evidence of potential carcinogenic risk to humans. Controversies arise when both positive and negative carcinogenicity data exist for a specific agent or when incomplete mechanistic data suggest a possible species difference in response. Issues of experimental design and evaluation that might contribute to disparate results are addressed in this article. To serve as reliable sources of data for the evaluation of the carcinogenic potential of environmental agents, experimental studies must include a) animal models that are sensitive to the end points under investigation; b) detailed characterization of the agent and the administered doses; c) challenging doses and durations of exposure (at least 2 years for rats and mice); d) sufficient numbers of animals per dose group to be capable of detecting a true effect; e) multiple dose groups to allow characterization of dose-response relationships, f) complete and peer-reviewed histopathologic evaluations; and g) pairwise comparisons and analyses of trends based on survival-adjusted tumor incidence. Pharmacokinetic models and mechanistic hypotheses may provide insights into the biological behavior of the agent; however, they must be adequately tested before being used to evaluate human cancer risk.

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Related in: MedlinePlus

Tumor dose–response curves: (A) five dose groups plus control; (B) a high-dose group, a much lower dose group, and control; (C) two low-dose groups plus control.
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f1-ehp0116-000130: Tumor dose–response curves: (A) five dose groups plus control; (B) a high-dose group, a much lower dose group, and control; (C) two low-dose groups plus control.

Mentions: Lower doses (1/2 MTD and 1/4 to 1/10 MTD) are used in case the highest dose selected for the chronic study is found to be too high (excessive mortality) and to provide information on dose–response relationships (Bucher et al. 1996). Pharmacokinetic information should also be used to ensure that no more than one of the selected doses is above a level that saturates the processes of absorption, metabolic activation, or detoxification. A cancer bioassay that uses only saturating doses would not be very informative in characterizing dose–response relationships at lower exposures. For example, carcinogenicity studies of 1,3-butadiene in rats were conducted with exposure concentrations of 1,000 and 8,000 ppm (Owen et al. 1987), although metabolism of this gas in rats is linear up to about 1,000 ppm (Bolt et al. 1984). A better characterization of the true dose–response can be achieved with larger numbers of properly spaced dose groups (Figure 1A) (e.g., five-dose study of 1,3-butadiene in mice at 6.25–625 ppm; Melnick et al. 1990) versus only two widely spaced dose groups (Figure 1B). Unless group size is extremely large (i.e., several hundred to thousands of animals per group), the selection of only low doses for the cancer bioassay or short exposure durations can lead to a misinterpretation of the carcinogenic potential of the agent under study and its potential risk at human exposure levels (Figure 1C). For example, chronic studies of p-dichlorobenzene failed to detect a carcinogenic effect in rats or mice exposed up to 500 ppm by inhalation for 76 or 57 weeks, respectively (Loeser and Litchfield 1983); in contrast, significant increases in kidney tumors in male rats and liver tumors in male and female mice were observed in 2-year gavage studies of p-dichlorobenzene at doses up to 300 or 600 mg/kg, respectively (NTP 1987).


Conflicting views on chemical carcinogenesis arising from the design and evaluation of rodent carcinogenicity studies.

Melnick RL, Thayer KA, Bucher JR - Environ. Health Perspect. (2008)

Tumor dose–response curves: (A) five dose groups plus control; (B) a high-dose group, a much lower dose group, and control; (C) two low-dose groups plus control.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2199296&req=5

f1-ehp0116-000130: Tumor dose–response curves: (A) five dose groups plus control; (B) a high-dose group, a much lower dose group, and control; (C) two low-dose groups plus control.
Mentions: Lower doses (1/2 MTD and 1/4 to 1/10 MTD) are used in case the highest dose selected for the chronic study is found to be too high (excessive mortality) and to provide information on dose–response relationships (Bucher et al. 1996). Pharmacokinetic information should also be used to ensure that no more than one of the selected doses is above a level that saturates the processes of absorption, metabolic activation, or detoxification. A cancer bioassay that uses only saturating doses would not be very informative in characterizing dose–response relationships at lower exposures. For example, carcinogenicity studies of 1,3-butadiene in rats were conducted with exposure concentrations of 1,000 and 8,000 ppm (Owen et al. 1987), although metabolism of this gas in rats is linear up to about 1,000 ppm (Bolt et al. 1984). A better characterization of the true dose–response can be achieved with larger numbers of properly spaced dose groups (Figure 1A) (e.g., five-dose study of 1,3-butadiene in mice at 6.25–625 ppm; Melnick et al. 1990) versus only two widely spaced dose groups (Figure 1B). Unless group size is extremely large (i.e., several hundred to thousands of animals per group), the selection of only low doses for the cancer bioassay or short exposure durations can lead to a misinterpretation of the carcinogenic potential of the agent under study and its potential risk at human exposure levels (Figure 1C). For example, chronic studies of p-dichlorobenzene failed to detect a carcinogenic effect in rats or mice exposed up to 500 ppm by inhalation for 76 or 57 weeks, respectively (Loeser and Litchfield 1983); in contrast, significant increases in kidney tumors in male rats and liver tumors in male and female mice were observed in 2-year gavage studies of p-dichlorobenzene at doses up to 300 or 600 mg/kg, respectively (NTP 1987).

Bottom Line: Underlying these uncertainties are issues related to how experiments are designed, how rigorously hypotheses are tested, and to what extent assertions extend beyond actual findings.Issues of experimental design and evaluation that might contribute to disparate results are addressed in this article.To serve as reliable sources of data for the evaluation of the carcinogenic potential of environmental agents, experimental studies must include a) animal models that are sensitive to the end points under investigation; b) detailed characterization of the agent and the administered doses; c) challenging doses and durations of exposure (at least 2 years for rats and mice); d) sufficient numbers of animals per dose group to be capable of detecting a true effect; e) multiple dose groups to allow characterization of dose-response relationships, f) complete and peer-reviewed histopathologic evaluations; and g) pairwise comparisons and analyses of trends based on survival-adjusted tumor incidence.

View Article: PubMed Central - PubMed

Affiliation: National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA. melnickr@niehs.nih.gov

ABSTRACT
Conflicting views have been expressed frequently on assessments of human cancer risk of environmental agents based on animal carcinogenicity data; this is primarily because of uncertainties associated with extrapolations of toxicologic findings from studies in experimental animals to human circumstances. Underlying these uncertainties are issues related to how experiments are designed, how rigorously hypotheses are tested, and to what extent assertions extend beyond actual findings. National and international health agencies regard carcinogenicity findings in well-conducted experimental animal studies as evidence of potential carcinogenic risk to humans. Controversies arise when both positive and negative carcinogenicity data exist for a specific agent or when incomplete mechanistic data suggest a possible species difference in response. Issues of experimental design and evaluation that might contribute to disparate results are addressed in this article. To serve as reliable sources of data for the evaluation of the carcinogenic potential of environmental agents, experimental studies must include a) animal models that are sensitive to the end points under investigation; b) detailed characterization of the agent and the administered doses; c) challenging doses and durations of exposure (at least 2 years for rats and mice); d) sufficient numbers of animals per dose group to be capable of detecting a true effect; e) multiple dose groups to allow characterization of dose-response relationships, f) complete and peer-reviewed histopathologic evaluations; and g) pairwise comparisons and analyses of trends based on survival-adjusted tumor incidence. Pharmacokinetic models and mechanistic hypotheses may provide insights into the biological behavior of the agent; however, they must be adequately tested before being used to evaluate human cancer risk.

Show MeSH
Related in: MedlinePlus