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Paracelsus to Parascience:
The Environmental Cancer Distraction

by Bruce N. Ames and Lois Swirsky Gold
September 7, 1999

1. Paracelsus to Parascience: The Dose (Trace) Makes the Poison

About 50% of chemicals — whether natural or synthetic — that have been tested in standard, high-dose, animal cancer tests are rodent carcinogens [1-3] (Table 1). What are the explanations for this high percentage? In standard cancer tests, rodents are given a chronic, near-toxic dose: 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 [2;4-14]. 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. Each time a cell divides, there is some probability that a mutation will occur, and thus increased cell division increases the risk of cancer. At the low levels of synthetic chemicals to which humans are usually exposed, such increased cell division does not occur. The process of mutagenesis and carcinogenesis is complicated because many factors are involved: e.g., DNA lesions, DNA repair, cell division, clonal instability, apoptosis, and p53 [15;16]. The normal endogenous level of oxidative DNA lesions in somatic cells is appreciable [17]. In addition, tissues injured by high doses of chemicals have an inflammatory immune response involving activation of white cells in response to cell death [18-25]. 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.

Is the high positivity rate due to selecting more suspicious chemicals to test? This 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 [9] is the high positivity rate for drugs (Table 1) because drug development tends to favor chemicals that are not mutagens or expected carcinogens. A second argument against selection bias is that the knowledge needed to predict carcinogenicity in rodent tests is highly imperfect, even now after decades of test results have become available on which to base predictions. 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 the level of accuracy varied by expert, thus indicating that predictive knowledge is highly uncertain [9;26]. Moreover, if the main basis for selection were suspicion rather than human exposure, then one should select mutagens (80% are positive compared to 50% of nonmutagens), yet 55% of the chemicals tested are nonmutagens [1;3;9].

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 [2;8;12-14;27]. 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 [7;28]. Regulatory agencies are moving slowly to take mechanism and non-linearity into account, e.g., U.S. EPA.

Linearity of dose-response seems unlikely in any case due to the inducibility of the numerous defense enzymes which deal with exogenous chemicals as groups, e.g., oxidants, electrophiles, and thus protect us against the natural world of mutagens as well as the small amounts of synthetic chemicals [29-32].

Article reprinted from Mutation Research Frontiers, 7 September 1999

Revised April 23, 2015