Misconceptions About Environmental Pollution, Pesticides and the Causes of Cancer

Policy Reports | Energy and Natural Resources

No. 214
Sunday, March 01, 1998
by Bruce N. Ames and Lois Swirsky Gold

Misconception #6: Cancer Risks to Humans Can Be Assessed By Standard High-Dose Animal Cancer Tests

"About 50 percent of all chemicals - natural or synthetic - that have been tested in standard, high-dose animal cancer tests are rodent carcinogens."

About 50 percent of all chemicals - whether natural or synthetic - that have been tested in standard, high-dose, animal cancer tests are rodent carcinogens.54 [See Appendix Table IV.] What are the explanations for this high percentage? In standard cancer tests rodents are given chronic, near-toxic doses - the maximum tolerated dose (MTD). Evidence is accumulating that cell division caused by the high dose itself, rather than the chemical per se, can contribute to cancer in these tests. 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.55 Each time a cell divides, the probability increases that a mutation will occur, thereby increasing the risk for cancer. At the low levels to which humans are usually exposed, such increased cell division does not occur. In addition, tissues injured by high doses of chemicals have an inflammatory immune response involving activation of white cells in response to cell death.56 Activated white cells release mutagenic oxidants (including peroxynitrite, hypochlorite, and hydrogen peroxide). Therefore, the very low levels of chemicals to which humans are exposed through water pollution or synthetic pesticide residues may pose no or minimal cancer risks.

The authors have discussed in another paper57 the argument that the high positivity rate is due to selecting more suspicious chemicals to test, which is a likely bias since cancer testing is both expensive and time-consuming, and it is prudent to test suspicious compounds. One argument against selection bias is the high positivity rate for drugs [see Appendix Table IV] because drug development tends to select chemicals that are not mutagens or expected carcinogens. A second argument against selection bias is that knowledge to predict carcinogenicity in rodent tests is highly imperfect, even now after decades of testing results have become available on which to base prediction. For example, a prospective prediction exercise was conducted by several experts in 1990 in advance of the two-year NTP bioassays. There was wide disagreement among them on which chemicals would be carcinogenic when tested, and accuracy varied, thus indicating that predictive knowledge is highly uncertain.58

"It seems likely that a high proportion of all chemicals, whether synthetic or natural, might be ‘carcinogens' if administered in high enough doses."

It seems likely that a high proportion of all chemicals, whether synthetic or natural, might be "carcinogens" if administered in the standard rodent bioassay at the maximum tolerated dose, primarily due to the effects of high doses on cell division and DNA damage.59 Without additional data on how a chemical causes cancer, the interpretation of a positive result in a rodent bioassay is highly uncertain. The induction of cancer could be the result of the high doses tested.

In regulatory policy, the "virtually safe dose" (VSD), corresponding to a maximum, hypothetical risk of one cancer in a million, is estimated from bioassay results using a linear model, which assumes that cancer causation is directly proportional to dose and that there are no unique effects of high doses. To the extent that carcinogenicity in rodent bioassays is due to the effects of high doses for the non-mutagens, and a synergistic effect of cell division at high doses with DNA damage for the mutagens, then this model is inappropriate. The EPA has recently proposed guidelines that permit the use of non-linear approaches to low dose extrapolation if warranted by mechanistic data and a possible threshold of dose below which effects will not occur.60

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