Approaches to assessing genetic risks from exposure to chemicals.

Abstract

An effort to assess and quantify genetic risks from human exposure to mutagenic chemicals is urgently needed; otherwise genetic toxicology may well lose its credibility. Genetic biomonitoring provides us with an indication of mutagenic effectiveness in human somatic cells. The populations and chemicals selected for such studies form a useful database for genetic risk-assessment studies. Extrapolation to what can be expected in germ cells of exposed individuals should be possible by using good dosimetry (adducts) and a parallelogram approach. The principle is that genetic damage in the inaccessible human germ cells can be estimated by determining the effects on lymphocytes (or other somatic cells) from humans and mice and in germ cells of mice. Worldwide, opportunities for the costly mouse germ cell studies are limited. Knowledge of type of DNA adducts, their persistence and/or removal and dominant lethal studies, will be helpful in predicting stage sensitivity. Extrapolation from a lowest effective dose level is proposed. The available data for ethylene oxide and benzene are reviewed. The risk of heritable translocations in progeny of populations exposed to ethylene oxide is so high that more precise estimates seem desirable. In discussing the expression of the induced mutations, the importance of dominant mutations and of heterozygous effects of deletions and other recessives is pointed out. The molecular changes underlying dominant mutations in man are more limited than is the case for recessive mutations. This raises the question whether mutagenic agents can produce the specific changes leading to recoverable, dominant mutations. Extrapolation from increased mutation rates to predictable increases of human disease, whether by doubling dose or direct methods, have been criticized.

Development of risk-based nanomaterial groups for occupational exposure control

“…Thus, a quantitative comparison of nanoparticle toxicity to benchmark particles (including consideration of the role physicalchemical properties) was suggested as a preferable method if sufficient data were available (Kuempel et al 2007). An example of a comparative toxicity approach (Schoeny and Margosches 1989) utilizes the "parallelogram" extrapolation method (Sobels 1993). These comparative toxicity analyses could be conducted in short-term assays for a set of nanomaterials in which the benchmark particles are the reference particles (e.g., positive and negative controls) to which the new materials would be compared (Fig.…”

Preconception exposure to mutagens: medical and other exposures to radiation and chemicals

“…1 Filling the void in understanding human germ cell mutagenesis (adapted from Sobels 1993) and other adverse genetic effects, namely a cohort approach.…”

“…The sustained work of James V. Neel and his colleagues was the search for genetic changes in the children of the American atomic bomb survivors in Japan (Neel and Schull 1991;Schull 2003). More than two decades ago, Sobels made a parallelogram that emphasized the void in understanding human germ cell mutagenesis (Sobels 1993; modified as Fig. 1).…”

Protection of the Gametes Embryo/Fetus From Prenatal Radiation Exposure

“…There are extensive data on mutations induced by ionizing radiation in microbes and somatic cells of rodents and humans. However, these data alone cannot be used to assess mutational risk in human germ cells, because the biological characteristics of human gametogenesis are different from that of other mammals and from somatic cells of either humans or other mammals (Sobels 1993). To accurately assess the influence of ionizing radiation on the genome of human germ cells, it is necessary to conduct studies in human populations.…”