Qualitative and quantitative procedures for health risk assessment.
Numerous reactive mutagenic electrophiles are present in the environment or are formed in the human body through metabolizing processes. Those electrophiles can directly react with DNA and are considered to be ultimate carcinogens. In the past decades more than 200 in vitro and in vivo genotoxic tests have been described to identify, monitor and characterize the exposure of humans to such agents. When the responses of such genotoxic tests are quantified by a weight-of-evidence analysis, it is found that the intrinsic potency of electrophiles being mutagens does not differ much for the majority of the agents studied. Considering the fact that under normal environmental circumstances human are exposed to low concentration of about a million electrophiles, the relation between exposure to such agents and adverse health effects (e.g., cancer) will become a 'Pandora's box'. For quantitative risk assessment it will be necessary not only to detect whether the agent is genotoxic, but also understand the mechanism of interaction of the agent with the DNA in target cells needs to be taken into account. Examples are given for a limited group of important environmental and carcinogenic agents for which such an approach is feasible. The groups identified are agents that form cross-links with DNA or are mono-alkylating agents that react with base-moieties in the DNA strands. Quantitative hazard ranking of the mutagenic potency of these groups of chemical can be performed and there is ample evidence that such a ranking corresponds with the individual carcinogenic potency of those agents in rodents. Still, in practice, with the exception of certain occupational or accidental exposure situations, these approaches have not be successful in preventing cancer death in the human population. However, this is not only due to the described 'Pandora's box' situation. At least three other factors are described. Firstly, in the industrial world the medical treatment of cancer in patients occurs with high levels of extremely mutagenic agents. Actually, both in number of persons and in exposure levels such medical treatment is the single largest exposure of humans to known carcinogens. Although such treatments are very effective in curing the tumor as present in the patient, the recurrence of cancer in those patients later in life is very high. In other words: "curing cancer is not the same as preventing cancer death in the human population". Secondly, the rate of cancer death in the human population is also determined by the efficacy in which other major causes of death are prevented. For instance, cardiovascular diseases are the major cause of death in humans in the industrialized world. There is evidence that the treatment of cardiovascular diseases is more successful than that of cancer. On a population level this will result in increase of cancer being the ultimate death cause. Finally, the improvement of medical treatment of diseases together with an improved quality of life will lead to increase average age of the population. Because the onset of most cancer is long after the exposure to carcinogens-in human often more than 30 years-cancer is predominantly a disease of the old age. This means that if the average age of human increases, there will be a selective preference of cancer becoming an even more important cause of death. This especially will be pronounced in those countries were the age distribution in a population is abnormal.
Lohman
P H
PH
Department of Radiation Genetics and Chemical Mutagenesis, Medical Genetic Center South-West the Netherlands, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, Netherlands. lohman@rullf2.medfac.leidenuniv.nl
D000375:Aging; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000633:toxicity*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004781:Environmental Exposure; D005260:Female; D006801:Humans; D008297:Male; D009152:Mutagenicity Tests / Q000379:methods / Q000706:statistics & numerical data; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D009369:Neoplasms / Q000209:etiology / Q000401:mortality / Q000517:prevention & control; D009426:Netherlands / Q000453:epidemiology; D011157:Population Dynamics; D018570:Risk Assessment / Q000379:methods*
D002274:Carcinogens, Environmental; D009153:Mutagens; D004247:DNA