Genotoxicity is a critical endpoint of toxicity to regulate environmental chemicals. Genotoxic chemicals are believed to have no thresholds for the action and impose genotoxic risk to humans even at very low doses. Therefore, genotoxic carcinogens, which induce tumors via genotoxic mechanisms, are regulated more strictly than non-genotoxic carcinogens, which induce tumors through non-genotoxic mechanisms such as hormonal effects, cell proliferation and cell toxicity. Although Ames bacterial mutagenicity assay is the gold standard to identify genotoxicity of chemicals, the genotoxicity should be further examined in rodents because Ames positive chemicals are not necessarily genotoxic in vivo. To better evaluate the genotoxicity of chemicals in a whole body system, gene mutation assays with gpt delta transgenic mice and rats have been developed. A feature of the assays is to detect point mutations and deletions by two distinct selection methods, ie, gpt and Spi− assays, respectively. The Spi− assay is unique in that it allows analyses of deletions and complex DNA rearrangements induced by double-strand breaks in DNA. Here, I describe the concept of gpt delta gene mutation assays and the application in food safety research, and discuss future perspectives of genotoxicity assays in vivo.
Aflatoxins are fungal toxins that possess acute life threatening toxicity, carcinogenic properties and other potential chronic adverse effects. Dietary exposure to aflatoxins is considered a major public health concern, especially for subsistence farming communities in sub-Saharan Africa and South Asia, where dietary staple food crops such as groundnuts and maize are often highly contaminated with aflatoxin due to hot and humid climates and poor storage, together with low awareness of risk and lack of enforcement of regulatory limits. Biomarkers have been developed and applied in many epidemiological studies assessing aflatoxin exposure and the associated health effects in these high-risk population groups. This review discusses the recent epidemiological evidence for aflatoxin exposure, co-exposure with other mycotoxins and associated health effects in order to provide evidence on risk assessment, and highlight areas where further research is necessary. Aflatoxin exposure can occur at any stage of life and is a major risk factor for hepatocellular carcinoma, especially when hepatitis B infection is present. Recent evidence suggests that aflatoxin may be an underlying determinant of stunted child growth, and may lower cell-mediated immunity, thereby increasing disease susceptibility. However, a causal relationship between aflatoxin exposure and these latter adverse health outcomes has not been established, and the biological mechanisms for these have not been elucidated, prompting further research. Furthermore, there is a dearth of information regarding the health effects of co-exposure to aflatoxin with other mycotoxins. Recent developments of biomarkers provide opportunities for important future research in this area.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of mepanipyrim (CAS No.110235-47-7), an anilinopyrimidine fungicide, based on results from various studies. Major adverse effects of mepanipyrim observed were hepatocellular hypertrophy, hepatocellular degeneration, and increased kidney weight in rats. Neither reproductive toxicity, teratogenicity nor genotoxicity was observed. Mepanipyrim (parent compound only) was identified as a chemical for the residue definition for dietary risk assessment in agricultural products. FSCJ adopted the no-observed-adverse-effect level (NOAEL) of 7.34 mg/kg bw/day, obtained in a two-year combined chronic/carcinogenicity study in rats, appropriate for specification of an acceptable daily intake (ADI). An ADI was thus specified as 0.073 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. The lowest NOAEL for adverse effects that would be likely to be elicited by a single oral administration of mepanipyrim was 400 mg/kg bw obtained in an acute neurotoxicity study in rats. Consequently, FSCJ specified an acute reference dose (ARfD) of 4 mg/kg bw, applying a safety factor of 100 to the NOAEL.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of an insecticide, abamectin (CAS No. 71751-41-2), based on results from various studies. The insecticide is consisted of avermectin B1a (CAS No. 65195-55-3) and avermectin B1b (CAS No. 65195-56-4), both macrolides having a structure of 16-membered ring. Major adverse effects of abamectin observed are neurological symptoms such as tremor/convulsion and mydriasis. FSCJ considered that abamectin causes tremor/convulsion through the GABA-ergic action with hyperpolarization of nerve/muscle cells. Neither carcinogenicity, reproductive toxicity, developmental neurotoxicity nor genotoxicity was observed. Based on the above results, abamectin and its isomeric 8,9-Z avermectin B1a, a photolytic product of avermectin B1a, were identified as chemicals for the residue definition for dietary risk assessment in agricultural products. The lowest value among the no-observed-adverse-effect levels (NOAELs) and the lowest-observed-adverse-effect levels (LOAELs) obtained in all the studies was the LOAEL of 0.12 mg/kg bw/day in a developmental neurotoxicity study in rats. FSCJ specified an acceptable daily intake (ADI) of 0.0006 mg/kg bw/day, applying a safety factor of 200 (10 for species difference, 10 for individual difference, and additional 2 for the use of LOAEL). The lowest NOAEL for adverse effects that would be likely to be elicited by a single oral administration of abamectin was 0.5 mg/kg bw/day consistently obtained in the acute neurotoxicity study in rats, and in the 18-week subacute toxicity study, the 85-day subacute toxicity study and the one-year chronic toxicity study in dogs. FSCJ specified an acute reference dose (ARfD) of 0.005 mg/kg bw, applying a safety factor of 100 to the NOAEL.