Comparison of carcinogenic and in vivo genotoxic potency estimates.
Mutagenic substances classified as carcinogens are primarily regulated on the basis of their carcinogenic effect. Regulation of mutagens that have not been tested for carcinogenicity represents a problem. In cases where a threshold cannot be identified, the substances may be banned or if their uses are deemed to be unavoidable, the exposure may be reduced to as low as technically and economically feasible. In an attempt to develop a procedure that may be helpful in regulation of mutagenic substances when studies on carcinogenicity are lacking, we have compared the lowest effective dose (LED) giving a response in an in vivo genotoxic test after oral or inhalation exposure with the carcinogenic dose descriptor T25 (the chronic daily dose which will give 25% of the animals tumours above background at a specific tissue site). The 34 carcinogens in the present analysis for which genotoxic mechanisms are likely or possible, represent different classes of carcinogens and different genotoxic endpoints, exhibiting carcinogenic and mutagenic potencies both covering a range of 10,000 between the most and least potent substances. A linear correlation was found between the lowest effective dose for in vivo genotoxicity after oral administration or inhalation exposure and the lowest dose descriptor T25 for tumour formation. The finding that the median of the ratio LED/T25 was 1.05 and that the ratio for 90% of the substances studied fell in the range 0.21 to 9.2 shows that the numerical value of LED is similar to the numerical value of T25 within a factor of 5-10. The results suggest that LED may be used as a basis for regulation of mutagens in cases where a threshold cannot be demonstrated or inferred, and where the substance has not been studied in long-term carcinogenicity studies. In such cases LED divided by a specified assessment factor may represent a virtually safe level or a tolerable risk level for a possible carcinogenic effect.
Sanner
Tore
T
Department of Environmental and Occupational Cancer, Institute for Cancer Research, The Norwegian Radium Hospital, N-0310 Oslo, Norway. tore.sanner@kjemi.uio.no
Dybing
Erik
E
D000280:Administration, Inhalation; D000284:Administration, Oral; D000820:Animal Diseases / Q000139:chemically induced; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000592:standards; D033181:Information Dissemination / Q000379:methods; D051379:Mice; D023421:Models, Animal; D009152:Mutagenicity Tests / Q000145:classification / Q000379:methods* / Q000592:standards; D009153:Mutagens / Q000008:administration & dosage* / Q000737:chemistry* / Q000633:toxicity; D051381:Rats; D018570:Risk Assessment / Q000331:legislation & jurisprudence / Q000379:methods / Q000592:standards
D002273:Carcinogens; D009153:Mutagens