An earlier review of the toxicity of glyphosate and the original Roundupä-branded formulation concluded that neither glyphosate nor the formulation poses a risk for the production of heritable/somatic mutations in humans. The present review of subsequent genotoxicity publications and regulatory studies of glyphosate and glyphosate-based formulations (GBFs) incorporates all of the findings into a weight of evidence for genotoxicity. An overwhelming preponderance of negative results in well-conducted bacterial reversion and in vivo mammalian micronucleus and chromosomal aberration assays indicates that glyphosate and typical GBFs are not genotoxic in these core assays. Negative results for in vitro gene mutation and a majority of negative results for chromosomal effect assays in mammalian cells add to the weight of evidence that glyphosate is not typically genotoxic for these endpoints in mammalian systems. Mixed results were observed for micronucleus assays of GBFs in nonmammalian systems. Reports of positive results for DNA damage endpoints indicate that glyphosate and GBFs tend to elicit DNA damage effects at high or toxic dose levels, but the data suggest that this is due to cytotoxicity rather than DNA interaction with GBF activity perhaps associated with the surfactants present in many GBFs. Glyphosate and typical GBFs do not appear to present significant genotoxic risk under normal conditions of human or environmental exposures.
Gene expression can be modulated in plants to produce desired traits through agricultural biotechnology. Currently, biotechnology-derived crops are compared to their conventional counterparts, with safety assessments conducted on the genetic modification and the intended and unintended differences. This review proposes that this comparative safety assessment paradigm is appropriate for plants modified to express mediators of RNA-mediated gene regulation, including RNA interference (RNAi), a gene suppression mechanism that naturally occurs in plants and animals. The molecular mediators of RNAi, including long double-stranded RNAs (dsRNA), small interfering RNAs (siRNA), and microRNAs (miRNA), occur naturally in foods; therefore, there is an extensive history of safe consumption. Systemic exposure following consumption of plants containing dsRNAs that mediate RNAi is limited in higher organisms by extensive degradation of ingested nucleic acids and by biological barriers to uptake and efficacy of exogenous nucleic acids. A number of mammalian RNAi studies support the concept that a large margin of safety will exist for any small fraction of RNAs that might be absorbed following consumption of foods from biotechnology-derived plants that employ RNA-mediated gene regulation. Food and feed derived from these crops utilizing RNA-based mechanisms is therefore expected to be as safe as food and feed derived through conventional plant breeding.
The Salmonella typhimurium microsomal test system for mutagenic activity was successfully used to detect the presence of mutagenic compounds in the smoke condensates of several types of cigarettes. The condensates were shown to contain compounds which could cause frameshift mutations when activated by microsomal enzymes. An analysis of fractions of smoke condensate revealed that the detected mutagenic activity was distributed in several of the fractions. Most of the activity of the whole condensate was in basic fractions and in a weakly acidic fraction. Condensates from cigarettes treated with magnesium nitrate differed from other condensates in two respects. They contained frameshift mutagens which did not require microsomal activation and mutagens which could cause base-pair substitution mutations. Although the detection system usually employs rat liver microsomal preparations, a rat lung microsomal preparation was also found to be capable of converting smoke condensates and known chemical carcinogens into mutagenic forms.In this laboratory a simple, quantitative, and sensitive bacterial assay system for the detection of mutagenic compounds has been developed (1-5). The system determines the ability of compounds to revert histidine auxotrophs of Salmonella typhimurium to histidine prototrophy, an event which requires mutation of the DNA. The use of a rat liver microsomal fraction in the assay system extends the scope of the system to include compounds which require nonbacterial metabolism for conversion into active mutagenic agents (6). A wide variety of carcinogens have been shown to be mutagens with this test system (1-6). This, and other work, showing that chemical carcinogens are mutagens strongly supports the appealing theory that cancer can be caused by somatic mutations (6). The economy of this bacterial assay suggests its usefulness as a tool in rapidly obtaining information about the potential mutagenic/careinogenic activity of uncharacterized compounds in complex mixtures.We have employed the Salmonella test system in characterizing cigarette smoke condensate, i.e., the particulate matter of cigarette smoke which contains over 1200 known components and many as yet unidentified compounds (reviewed in ref. 7). Cigarette smoke condensate is known to act as a carcinogen and cocarcinogen in mouse skin tests (8,9), and statistical evidence indicates that cigarette smoke is a contributing factor in the cause of human cancer (10-12).We were able to demonstrate that cigarette smoke condensates have mutagenic activity. The assay system enabled us to assess the type of mutagenic activity present and the role of mammalian metabolism in the expression of this mutagenic activity. We have also examined fractions of the cigarette smoke condensate to determine the distribution of the de-4159 tected mutagenic activity among the classes of chemical compounds which are separated by the fractionation procedure. MATERIALS AND METHODSBacterial Strains. The Salmbnella typhimurium strains used, TA1535, TA1536, TA1537...
The International Agency for Research on Cancer (IARC) published a monograph in 2015 concluding that glyphosate is "probably carcinogenic to humans" (Group 2A) based on limited evidence in humans and sufficient evidence in experimental animals. It was also concluded that there was strong evidence of genotoxicity and oxidative stress. Four Expert Panels have been convened for the purpose of conducting a detailed critique of the evidence in light of IARC's assessment and to review all relevant information pertaining to glyphosate exposure, animal carcinogenicity, genotoxicity, and epidemiologic studies. Two of the Panels (animal bioassay and genetic toxicology) also provided a critique of the IARC position with respect to conclusions made in these areas. The incidences of neoplasms in the animal bioassays were found not to be associated with glyphosate exposure on the basis that they lacked statistical strength, were inconsistent across studies, lacked dose-response relationships, were not associated with preneoplasia, and/or were not plausible from a mechanistic perspective. The overall weight of evidence from the genetic toxicology data supports a conclusion that glyphosate (including GBFs and AMPA) does not pose a genotoxic hazard and therefore, should not be considered support for the classification of glyphosate as a genotoxic carcinogen. The assessment of the epidemiological data found that the data do not support a causal relationship between glyphosate exposure and nonHodgkin's lymphoma while the data were judged to be too sparse to assess a potential relationship between glyphosate exposure and multiple myeloma. As a result, following the review of the totality of the evidence, the Panels concluded that the data do not support IARC's conclusion that glyphosate is a "probable human carcinogen" and, consistent with previous regulatory assessments, further concluded that glyphosate is unlikely to pose a carcinogenic risk to humans. ARTICLE HISTORY
published a monograph concluding there was strong evidence for genotoxicity of glyphosate and glyphosate formulations and moderate evidence for genotoxicity of the metabolite aminomethylphosphonic acid (AMPA). These conclusions contradicted earlier extensive reviews supporting the lack of genotoxicity of glyphosate and glyphosate formulations. The IARC Monograph concluded there was strong evidence of induction of oxidative stress by glyphosate, glyphosate formulations, and AMPA. The Expert Panel reviewed the genotoxicity and oxidative stress data considered in the IARC Monograph, together with other available data not considered by IARC. The Expert Panel defined and used a weight of evidence (WoE) approach that included ranking of studies and endpoints by the strength of their linkage to events associated with carcinogenic mechanisms. Importantly, the Expert Panel concluded that there was sufficient information available from a very large number of regulatory genotoxicity studies that should have been considered by IARC. The WoE approach, the inclusion of all relevant regulatory studies, and some differences in interpretation of individual studies led to significantly different conclusions by the Expert Panel compared with the IARC Monograph. The Expert Panel concluded that glyphosate, glyphosate formulations, and AMPA do not pose a genotoxic hazard and the data do not support the IARC Monograph genotoxicity evaluation. With respect to carcinogenicity classification and mechanism, the Expert Panel concluded that evidence relating to an oxidative stress mechanism of carcinogenicity was largely unconvincing and that the data profiles were not consistent with the characteristics of genotoxic carcinogens. ARTICLE HISTORY
Mutations in Salmonella typhimurium strains lacking nonspecific acid phosphatase mapped in two unlinked loci. One of these, phoP, was cotransducible by phage P22 with purB, whereas the second, phoN, was cotransducible by phage P1 with purA. Mutants with temperature-sensitive nonspecific acid phosphatase activity (measured in whole cells) were also isolated. A phoN mutant with thermolabile whole-cell activity was isolated directly from wild-type LT-2. Several other mutants with temperature-sensitive enzyme activity were also isolated as revertants ofphoN mutants. These data suggest that phoN might be a structural locus for nonspecific acid phosphatase. The observation that a mutation resulting in high levels of nonspecific acid phosphatase mapped inphoP suggests a possible regulatory role for this locus.
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