Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol-Certain health supplements may cause both carcinogenic and anticarcinogenic effects

Frank Johnson and James Huff

National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA

Stoner et al. (1) described a multi-organ rat model, following earlier work (2,3), and analyzed the effects of indole-3-carbinol (I-3-C) on 7,12-dimethylbenz[a]anthracene (DMBA)-, azoxymethane (AOM)- and aflatoxin B1 (AFB1)-induced tumor development in colon, mammary gland and liver. They reported that although I-3-C is sold without prescription as an antiestrogenic chemopreventive agent in health food stores, a combination of anticarcinogenic and carcinogenic effects were induced in their model system. Thus, I-3-C appears to retard the rate of mammary tumor development by extending latency, but does not seem to affect mammary tumor incidence, tumor multiplicity or survival. Furthermore, I-3-C resulted in a decrease in aberrant colon crypt foci, but in the liver the chemical induced formation of GST-P foci. Because of the mixed effects, Stoner et al. (1) cautioned against the use of I-3-C as a chemopreventive agent in humans.

We wish to extend these recent observations by stressing that combinations of anticarcinogenic and carcinogenic effects are a relatively common occurrence in studies where rodents are subjected to long-term chemical exposures at maximum tolerated doses (4,5). In some cases, one sex or strain may show a chemically related increase in tumor incidence while another sex or strain may show a chemically related decrease. For such cases, the particular tissue/organ sites in which the tumor development is affected (enhanced or retarded) may be the same or different in different groups of animals. In other cases, one group of chemically treated animals might show both an increase in tumor incidence at one tissue organ/site and a decrease in tumor incidence at a different tissue/organ site.

Chemical exposure may also result in reduced survival for a variety of reasons, including induction of rapidly lethal tumors, which precludes the appearance of tumors that might typically appear later in life (6,7). In some National Toxicology Program (NTP) rodent tests, however, chemical exposure results in improved rather than diminished survival, although chemicals administered in the feed tend to show improved survival more often than chemicals administered by other routes (4).

Chemicals that induce mixed effects are appropriately referred to as Janus (traditionally depicted as having two faces looking in opposite directions) carcinogens (8). And in rodent tests conducted by the NTP many chemicals classified as carcinogens show a Janus effect (5). All known human carcinogens that have been tested have also been shown to induce carcinogenic effects in animals, and for some of these the first evidence was seen in animals (9–11). Overall though, few human carcinogens have been tested systematically in a standardized test system as used by the NTP (5,12). Some examples of human carcinogens tested by the NTP include benzene, benzidine dyes, bischloromethylethylether, 1,3-butadiene and ethylene oxide. Thus, the extent to which human carcinogens are Janus carcinogens is not known, but based on tests of many different kinds of chemicals in rats and mice, human carcinogens might be expected to show Janus effects as well. This seems to be the case with many of the anticancer chemotherapeutic agents in current use: that is, both prevent cancer and often later also induce secondary cancer.

A host of other variables may also influence the carcinogenic response in animal cancer tests (including dose, route of administration, sex, strain and species) all of which may interact to increase or decrease tumor incidence and alter quality and length of life (12–14). Taking these variables into consideration would likely further increase the proportion of chemicals that would be discovered to be Janus carcinogens if more tests were done. The Janus effect that Stoner et al. (1) reported for I-3-C seems likely to apply to chemical exposures in general, regardless of whether a chemical is recognized as a carcinogen, anticarcinogen or non-carcinogen.

As in the case of pharmaceutical agents, the use of health supplements may result in benefits as well as possible adverse consequences. Drugs, however, are generally prescribed to alleviate existing conditions, many of which may be serious health threats, and mild or rare adverse reactions are regarded as an acceptable trade-off. Conversely, health supplements may be purchased and consumed by anyone, healthy or not. These are generally not regulated. The decision for a healthy person to take a health supplement should consider that while the supplement may provide some benefit it may also cause an unexpected adverse effect and may well have an unpredictable combination of beneficial and harmful effects depending on health, sex, age, diet, amount of the substance consumed, genetic make-up, life-style factors such as alcoholism, and so on. That some not yet expressed, unknown, adverse condition will be improved is perhaps also possible, but hardly a reason to accept the possible risk of adverse effects. Exception to this are known genetic conditions, such as metabolic diseases, the effects of which are predictable and can often be overcome with proper treatment. Generally, though, a knowledge base is lacking to recommend health supplements to improve quality of life and prevent occurrence of unspecific disease conditions.

An example of a supplement that was once touted as a likely chemopreventive anticarcinogen is beta-carotene (15,16). However, more recent efforts have questioned the efficacy of beta-carotene (16,17) and in trials, smokers administered a beta-carotene supplement showed an increased risk of lung cancer and increased overall mortality as well (16,18). An example of a drug that both decreases and increases the risk of cancer is tamoxifen, which provides some protection against the occurrence and reoccurrence of breast cancer in women, but at the same time increases the risk of uterine cancer (19,20). Milk thistle extract (containing silymarin), grape seed extract (proanthocyanidins), green tea extract (catechins), garlic extract (selenium), red wine (resveratrol), tomatoes (lycopene), red clover (isoflavones) and vitamin E, are examples of a large number of other readily available substances that have been suggested to be possible anticarcinogens (Supplement Watch, http://www.supplementwatch.com/supcat/category.asp).

The concern Stoner et al. (1) have for adverse consequences from the health supplement I-3-C needs to be taken seriously and should probably be expanded to cover health supplements in general as an important public health issue.

Notes

Emails: johnson1{at}niehs.nih.gov and huff1{at}niehs.nih.gov

References

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Received May 29, 2002; revised June 24, 2002; accepted July 2, 2002.