Application of integrated genetic monitoring: the optimal approach for detecting environmental carcinogens.

Short-term in vitro genetic toxicity assays have not fulfilled their anticipated role in predicting the carcinogenicity of environmental agents reliably and economically. A reduction in emphasis from nonanimal systems to relevant animal assays and population monitoring will help to reestablish the credibility of this field. An analysis of the various steps in the carcinogenic process indicates the biological responses occurring during these stages can be utilized for early detection of environmental carcinogens. Emphasis should be placed on using the earliest significant response that indicates genetic damage (e.g., gene mutations and chromosome alterations). Assays that detect pregenomic damage (e.g., adduct formation), without evidence of subsequent heritable genetic alterations, may produce misleading results for risk assessment and should not be considered as stand-alone monitoring procedures. Late biological responses may occur in tissues or organs where genetic damage may be difficult to measure, and the opportunity for intervention diminishes as we approach the clinical outcome. For example, analyzing localized cells that contain activated protooncogenes and inactivated tumor suppressor genes, although they further document adverse response from exposure to carcinogens, may be of greater value for indicating clinical outcome than for genetic monitoring. With few notable exceptions, the window of opportunity for genetic monitoring is the period after exposure where genetic damage is evident and where circulating lymphocytes can faithfully record this damage. An ongoing study of butadiene-exposed workers illustrates an optimum protocol, where multiple assays can be carried out and correlated with both external and internal measurements of exposure.(ABSTRACT TRUNCATED AT 250 WORDS)