Environmental fate of monosodium methanearsonate (MSMA)-Part 2: Modeling sequestration and transformation.

Monosodium methanearsonate (MSMA), a sodium salt of monomethylarsonic acid (MMA), is a selective contact herbicide used for the control of a broad spectrum of weeds. In water, MSMA dissociates to ions of sodium (Na+) and monomethylarsonate (MMA-) that is stable and does not transform abiotically. In soils characteristic of MSMA use, several simultaneous processes can occur: (1) microbial methylation of MMA to dimethylarsinic acid (DMA), (2) microbial demethylation of MMA to inorganic arsenic (iAs), (3) methylation of iAs to MMA, and (4) sorption and sequestration of MMA and its metabolites to soil minerals. Sequestered residues are residues that cannot be desorbed from soil in environmental conditions. Sequestration is rapid in the initial several days after MSMA application and continues at a progressively slower rate over time. Once sequestered, MMA and its metabolites are inaccessible to soil microorganisms and cannot be transformed. The rate and extent of the sorption and sequestration as well as the mobility of MMA and its metabolites depend on the local edaphic conditions. In typical MSMA use areas, the variability of the edaphic conditions is constrained. The goal of this research was to estimate the amount of iAs potentially added to drinking water as a result of the use of MSMA, with models and scenarios developed by the US Environmental Protection Agency for pesticide risk assessment. In this project, the estimated drinking water concentrations (EDWCs) for iAs were assessed as the average concentration in the reservoir over a 30-year simulation with annual applications of MSMA at maximum label rates. When the total area of suitable land was assumed to be treated, EDWCs ranged from <0.001 to 0.12 µg/L. When high estimates of actually treated acreage are considered, the EDWCs are below 0.06 µg/L across all scenarios. Integr Environ Assess Manag 2024;00:1-12. © 2024 The Author(s). Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Environmental fate of monosodium methanearsonate (MSMA)-Part 1: Conceptual model.

Monosodium methanearsonate (MSMA), the sodium salt of monomethylarsonic acid (MMA), is used as a selective, broad-spectrum contact herbicide to control weeds in cotton and a variety of turf. In water, MSMA dissociates into ions of sodium (Na+) and of MMA-, which is the herbicide's active component. Certain soil microorganisms can methylate MMA to dimethylarsinic acid (DMA) other microorganisms can demethylate MMA to inorganic arsenic (iAs). To predict the groundwater concentration of iAs that may result from MSMA application, the processes affecting the environmental behavior of MSMA must be quantified and modeled. There is an extensive body of literature regarding the environmental behavior of MSMA. There is a consensus among scientists that the fate of MMA in soil is controlled by microbial activity and sorption to solid surfaces and that iAs sorption is even more extensive than that of MMA. The sorption and transformation of MMA and its metabolites are affected by several factors including aeration condition, temperature, pH, and the availability of nutrients. The precise nature and extent of each of these processes vary depending on site-specific conditions; however, such variability is constrained in typical MSMA use areas that are highly managed. Monomethylarsonic acid is strongly sorbed on mineral surfaces and becomes sequestered into the soil matrix. Over time, a greater portion of MMA and iAs becomes immobile and unavailable to soil microorganisms and to leaching. This review synthesizes the results of studies that are relevant for the behavior of MSMA used as a herbicide to reliably predict the fate of MSMA in its use conditions. Integr Environ Assess Manag 2024;00:1-17. © 2024 The Author(s). Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

The clinical and laboratory spectrum of dedicator of cytokinesis 8 immunodeficiency syndrome in patients with a unique mutation.

Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency usually diagnosed as autosomal recessive hyper IgE syndrome. We sought to reveal the varying manifestations in patients with a unique mutation in DOCK8 gene by a retrospective medical record review. Ten patients from five consanguineous families and three tribes were included. Seven patients were homozygous for the c.C5134A, p.S1711X mutation, and the remaining three patients were their siblings manifesting hyper IgE syndrome features without a genetic diagnosis. Prior to the genetic diagnosis, the clinical diagnosis was "hyper IgE syndrome" in six patients and "anti-pneumococcal antibody deficiency," "recurrent pneumonia with bronchiectasis," and "asthma with hypereosinophilic syndrome" each diagnosed once. One additional patient was diagnosed due to family history. The age of presentation varied from 1 to 16 months. Eczema was diagnosed in all patients, food allergies in three, and severe herpes keratitis or malignancy or autoimmunity in two patients. Elevated IgE was recorded in nine patients; however, in six patients, the initial serum IgE concentration was equal to or less than three times the normal concentration for age, and in these patients, the median age at IgE evaluation was 7.5 months compared with 21.5 months in patients with an initial IgE concentration above three times the normal concentration for age (P = 0.067). The spectrum of disease manifestations in patients with a unique mutation in DOCK8 is variable. The genotype-phenotype correlations may be modified by genetic and/or epigenetic modifiers beyond the monogenic effect. Younger patients tend to have lower IgE concentrations at the initial measurement of IgE.

Evaluation of the carcinogenicity of inorganic arsenic.

Inorganic arsenic (iAs) at high exposures is a human carcinogen, affecting mainly the urinary bladder, lung and skin. We present an assessment of the mode of action (MOA) of iAs's carcinogenicity based on the United States Environmental Protection Agency/International Programme on Chemical Safety (USEPA/IPCS) framework, focusing primarily on bladder cancer. Evidence is presented for a MOA involving formation of reactive trivalent metabolites interacting with critical cellular sulfhydryl groups, leading to cytotoxicity and regenerative cell proliferation. Metabolism, kinetics, cell transport, and reaction with specific proteins play a critical role in producing the effects at the cellular level, regardless of cell type, whether urothelium, lung epithelium or epidermis. The cytotoxicity induced by iAs results in non-cancer toxicities, and the regenerative cell proliferation enhances development of epithelial cancers. In other tissues, such as vascular endothelium, different toxicities develop, not cancer. Evidence supporting this MOA comes from in vitro investigations on animal and human cells, from animal models, and from epidemiological studies. This MOA implies a non-linear, threshold dose-response relationship for both non-cancer and cancer end points. The no effect levels in animal models (approximately 1 ppm of water or diet) and in vitro (>0.1 µM trivalent arsenicals) are strikingly consistent. Cancer effects of iAs in humans generally are not observed below exposures of 100-150 ppb in drinking water: below these exposures, human urine concentrations of trivalent metabolites are generally below 0.1 µM, a concentration not associated with bladder cell cytotoxicity in in vitro or animal models. Environmental exposures to iAs in most of the United States do not approach this threshold.

Methylated arsenicals: the implications of metabolism and carcinogenicity studies in rodents to human risk assessment.

Monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)) are active ingredients in pesticidal products used mainly for weed control. MMA(V) and DMA(V) are also metabolites of inorganic arsenic, formed intracellularly, primarily in liver cells in a metabolic process of repeated reductions and oxidative methylations. Inorganic arsenic is a known human carcinogen, inducing tumors of the skin, urinary bladder, and lung. However, a good animal model has not yet been found. Although the metabolic process of inorganic arsenic appears to enhance the excretion of arsenic from the body, it also involves formation of methylated compounds of trivalent arsenic as intermediates. Trivalent arsenicals (whether inorganic or organic) are highly reactive compounds that can cause cytotoxicity and indirect genotoxicity in vitro. DMA(V) was found to be a bladder carcinogen only in rats and only when administered in the diet or drinking water at high doses. It was negative in a two-year bioassay in mice. MMA(V) was negative in 2-year bioassays in rats and mice. The mode of action for DMA(V)-induced bladder cancer in rats appears to not involve DNA reactivity, but rather involves cytotoxicity with consequent regenerative proliferation, ultimately leading to the formation of carcinoma. This critical review responds to the question of whether DMA(V)-induced bladder cancer in rats can be extrapolated to humans, based on detailed comparisons between inorganic and organic arsenicals, including their metabolism and disposition in various animal species. The further metabolism and disposition of MMA(V) and DMA(V) formed endogenously during the metabolism of inorganic arsenic is different from the metabolism and disposition of MMA(V) and DMA(V) from exogenous exposure. The trivalent arsenicals that are cytotoxic and indirectly genotoxic in vitro are hardly formed in an organism exposed to MMA(V) or DMA(V) because of poor cellular uptake and limited metabolism of the ingested compounds. Furthermore, the evidence strongly supports a nonlinear dose-response relationship for the biologic processes involved in the carcinogenicity of arsenicals. Based on an overall review of the evidence, using a margin-of-exposure approach for MMA(V) and DMA(V) risk assessment is appropriate. At anticipated environmental exposures to MMA(V) and DMA(V), there is not likely to be a carcinogenic risk to humans.

Dimethylarsinic acid: results of chronic toxicity/oncogenicity studies in F344 rats and in B6C3F1 mice.

Dimethylarsinic acid (DMA(V), cacodylic acid), a foliar herbicide, was administered in the diet to B6C3F1 mice (at dose levels of 0, 8, 40, 200, and 500 ppm) and to F344 rats (at dose levels of 0, 2, 10, 40, and 100 ppm) for 2 years, according to US EPA guidelines. In mice, there were no treatment-related tumors observed at any site. Treatment-related progressive glomerulonephropathy and nephrocalcinosis were observed in the kidneys in both sexes. The incidence of vacuolation of the epithelium in the urinary bladder was increased in both sexes, but was not associated with cytotoxicity, necrosis or hyperplasia. Based on non-neoplastic lesions found in the urinary bladder, the NOEL for mice was assessed to be 40 ppm in males and 8 ppm in females. In rats, treatment-related mortality occurred early in the study in five males in the 100 ppm group and in one male in the 40 ppm group. Papillomas and carcinomas with degeneration of the urothelium, necrosis and urothelial cell hyperplasia, were found in the urinary bladders of both sexes. In male rats, one papilloma was found in each of the 10 and 40 ppm groups; one urothelial cell carcinoma was found in the 2 ppm group and two in the 100 ppm group. Four papillomas and six urothelial cell carcinomas were found in the female 100 ppm group. Non-neoplastic treatment-related kidney lesions were confined to the 40 and 100 ppm levels and included necrosis, pyelonephritis, medullary nephrocalcinosis and tubular cystic dilation, hyperplasia of the epithelial lining of the papilla, and pelvic urothelial cell hyperplasia. All of these kidney changes appear to be related to an increase in the aging nephropathy of the rat. Dose-related increases in the height of the thyroid follicular epithelium were also noted in males and females, however, such changes reflect an adaptive response of the thyroid to decreased levels of circulating thyroid hormone, rather than an adverse effect. Based on the kidney and bladder lesions, the NOEL for non-neoplastic and neoplastic lesions was considered to be 10 ppm in males and females. Based on these studies, DMA(V) is carcinogenic only in rats and only at relatively high doses, with the urinary bladder as the target organ. Female rats appear to be more sensitive to the effects of DMA(V) than male rats. DMA(V) is not carcinogenic in mice.

Chronic studies evaluating the carcinogenicity of monomethylarsonic acid in rats and mice.

Monomethylarsonic acid (MMA) was administered in the diet of male and female Fischer F344 rats and B6C3F1 mice in 2-year feeding studies according to US EPA guidelines. Rats were treated with 50, 400, or 1300 ppm MMA and mice were treated with 10, 50, 200, or 400 ppm MMA based on preliminary short-term studies. The highest dose in the male and female rat groups was reduced to 1000 ppm during week 53 and then further reduced to 800 ppm during week 60 due to high mortality in the male rats. There was no treatment-related mortality in the mice. The primary target organ for MMA-induced toxicity in rats and mice was the large intestine. Toxicity was more severe in rats compared to mice and in male rats compared to female rats. The maximum tolerated dose for chronic dietary administration of MMA in rats and mice was assessed as 400 ppm, and the no effect level with regard to intestinal toxicity was assessed as 50 ppm for rats and female mice and 200 ppm for male mice. There were no treatment-related neoplastic effects detected in either the rat or the mouse.