Regulatory Cancer Risk Assessment Based on a Quick Estimate of a Benchmark Dose Derived from the Maximum Tolerated Dose

Pesticide Residues in Food and Cancer Risk: A Critical Analysis

“…Several of our findings in large-scale analyses of the results of animal cancer tests are consistent with the idea that cell division increases the carcinogenic effect in high-dose bioassays, including the high proportion of chemicals that are positive; the high proportion of rodent carcinogens that are not mutagenic; and the fact that mutagens, which can both damage DNA and increase cell division at high doses, are more likely than nonmutagens to be positive, to induce tumors in both rats and mice, and to induce tumors at multiple sites (Gold et al, , 1998. Analyses of the limited data on dose response in bioassays are consistent with the idea that cell division from cell killing and cell replacement is important.…”

“…Evidence is accumulating that cell division caused by the high dose itself, rather than the chemical per se, contributes to cancer in such tests (Ames and Gold, 1990;Ames et al, 1993a;Butterworth and Bogdanffy, 1999;Cohen, 1998;Cunningham, 1996;Heddle, 1998). High doses can cause chronic wounding of tissues, cell death, and consequent chronic cell division of neighboring cells, which is a risk factor for cancer (Ames and Gold, 1990;Gold et al, 1998). Each time a cell divides, there is some probability that a mutation will occur, and thus increased cell division increases the risk of cancer.…”

“…Although cell division is not measured in routine cancer tests, many studies on rodent carcinogenicity show a correlation between cell division at the MTD and cancer Gold et al, 1998;Hayward et al, 1995). Extensive reviews of bioassay results document that chronic cell division can induce cancer (Ames and Gold, 1990;Ames et al, 1993b;Cohen, 1995b;Cohen and Ellwein, 1991;Cohen and Lawson, 1995;Counts and Goodman, 1995;Gold et al, 1997b).…”

“…To the extent that carcinogenicity in rodent bioassays is due to the effects of high doses for the nonmutagens, and a synergistic effect of cell division at high doses with DNA damage for the mutagens, this model overestimates risk (Butterworth and Bogdanffy, 1999;Gaylor and Gold, 1998).…”

“…We have discussed validity problems associated with the use of the limited data from animal cancer tests for human risk assessment (Bernstein et al, 1985;Gold et al, 1998). Standard practice in regulatory risk assessment for a given rodent carcinogen has been to extrapolate from the high doses of rodent bioassays to the low doses of most human exposures by multiplying carcinogenic potency in rodents by human exposure.…”