Environmental plastics in the context of UV radiation, climate change, and the Montreal Protocol.

There are close links between solar UV radiation, climate change, and plastic pollution. UV-driven weathering is a key process leading to the degradation of plastics in the environment but also the formation of potentially harmful plastic fragments such as micro- and nanoplastic particles. Estimates of the environmental persistence of plastic pollution, and the formation of fragments, will need to take in account plastic dispersal around the globe, as well as projected UV radiation levels and climate change factors.

Plastics in the environment in the context of UV radiation, climate change and the Montreal Protocol: UNEP Environmental Effects Assessment Panel, Update 2023.

This Assessment Update by the Environmental Effects Assessment Panel (EEAP) of the United Nations Environment Programme (UNEP) considers the interactive effects of solar UV radiation, global warming, and other weathering factors on plastics. The Assessment illustrates the significance of solar UV radiation in decreasing the durability of plastic materials, degradation of plastic debris, formation of micro- and nanoplastic particles and accompanying leaching of potential toxic compounds. Micro- and nanoplastics have been found in all ecosystems, the atmosphere, and in humans. While the potential biological risks are not yet well-established, the widespread and increasing occurrence of plastic pollution is reason for continuing research and monitoring. Plastic debris persists after its intended life in soils, water bodies and the atmosphere as well as in living organisms. To counteract accumulation of plastics in the environment, the lifetime of novel plastics or plastic alternatives should better match the functional life of products, with eventual breakdown releasing harmless substances to the environment.

Assessment of risks to listed species from the use of atrazine in the USA: a perspective.

Atrazine is a triazine herbicide used predominantly on corn, sorghum, and sugarcane in the US. Its use potentially overlaps with the ranges of listed (threatened and endangered) species. In response to registration review in the context of the Endangered Species Act, we evaluated potential direct and indirect impacts of atrazine on listed species and designated critical habitats. Atrazine has been widely studied, extensive environmental monitoring and toxicity data sets are available, and the spatial and temporal uses on major crops are well characterized. Ranges of listed species are less well-defined, resulting in overly conservative designations of "May Effect". Preferences for habitat and food sources serve to limit exposure among many listed animal species and animals are relatively insensitive. Atrazine does not bioaccumulate, further diminishing exposures among consumers and predators. Because of incomplete exposure pathways, many species can be eliminated from consideration for direct effects. It is toxic to plants, but even sensitive plants tolerate episodic exposures, such as those occurring in flowing waters. Empirical data from long-term monitoring programs and realistic field data on off-target deposition of drift indicate that many other listed species can be removed from consideration because exposures are below conservative toxicity thresholds for direct and indirect effects. Combined with recent mitigation actions by the registrant, this review serves to refine and focus forthcoming listed species assessment efforts for atrazine.Abbreviations: a.i. = Active ingredient (of a pesticide product). AEMP = Atrazine Ecological Monitoring Program. AIMS = Avian Incident Monitoring SystemArach. = Arachnid (spiders and mites). AUC = Area Under the Curve. BE = Biological Evaluation (of potential effects on listed species). BO = Biological Opinion (conclusion of the consultation between USEPA and the Services with respect to potential effects in listed species). CASM = Comprehensive Aquatic System Model. CDL = Crop Data LayerCN = field Curve Number. CRP = Conservation Reserve Program (lands). CTA = Conditioned Taste Avoidance. DAC = Diaminochlorotriazine (a metabolite of atrazine, also known by the acronym DACT). DER = Data Evaluation Record. EC25 = Concentration causing a specified effect in 25% of the tested organisms. EC50 = Concentration causing a specified effect in 50% of the tested organisms. EC50RGR = Concentration causing a 50% reduction in relative growth rate. ECOS = Environmental Conservation Online System. EDD = Estimated Daily Dose. EEC = Expected Environmental Concentration. EFED = Environmental Fate and Effects Division (of the USEPA). EFSA = European Food Safety Agency. EIIS = Ecological Incident Information System. ERA = Environmental Risk Assessment. ESA = Endangered Species Act. ESU = Evolutionarily Significant UnitsFAR = Field Application RateFIFRA = Federal Insecticide, Fungicide, and Rodenticide Act. FOIA = Freedom of Information Act (request). GSD = Genus Sensitivity Distribution. HC5 = Hazardous Concentration for ≤ 5% of species. HUC = Hydrologic Unit Code. IBM = Individual-Based Model. IDS = Incident Data System. KOC = Partition coefficient between water and organic matter in soil or sediment. KOW = Octanol-Water partition coefficient. LC50 = Concentration lethal to 50% of the tested organisms. LC-MS-MS = Liquid Chromatograph with Tandem Mass Spectrometry. LD50 = Dose lethal to 50% of the tested organisms. LAA = Likely to Adversely Affect. LOAEC = Lowest-Observed-Adverse-Effect Concentration. LOC = Level of Concern. MA = May Affect. MATC = Maximum Acceptable Toxicant Concentration. NAS = National Academy of Sciences. NCWQR = National Center of Water Quality Research. NE = No Effect. NLAA = Not Likely to Adversely Affect. NMFS = National Marine Fisheries Service. NOAA = National Oceanic and Atmospheric Administration. NOAEC = No-Observed-Adverse-Effect Concentration. NOAEL = No-Observed-Adverse-Effect Dose-Level. OECD = Organization of Economic Cooperation and Development. PNSP = Pesticide National Synthesis Project. PQ = Plastoquinone. PRZM = Pesticide Root Zone Model. PWC = Pesticide in Water Calculator. QWoE = Quantitative Weight of Evidence. RGR = Relative growth rate (of plants). RQ = Risk Quotient. RUD = Residue Unit Doses. SAP = Science Advisory Panel (of the USEPA). SGR = Specific Growth Rate. SI = Supplemental Information. SSD = Species Sensitivity Distribution. SURLAG = Surface Runoff Lag Coefficient. SWAT = Soil & Water Assessment Tool. SWCC = Surface Water Concentration Calculator. UDL = Use Data Layer (for pesticides). USDA = United States Department of Agriculture. USEPA = United States Environmental Protection Agency. USFWS = United States Fish and Wildlife Service. USGS = United States Geological Survey. WARP = Watershed Regressions for Pesticides.

Ecotoxicology of Glyphosate, Its Formulants, and Environmental Degradation Products.

The chemical and biological properties of glyphosate are key to understanding its fate in the environment and potential risks to non-target organisms. Glyphosate is polar and water soluble and therefore does not bioaccumulate, biomagnify, or accumulate to high levels in the environment. It sorbs strongly to particles in soil and sediments and this reduces bioavailability so that exposures to non-target organisms in the environment are acute and decrease with half-lives in the order of hours to a few days. The target site for glyphosate is not known to be expressed in animals, which reduces the probability of toxicity and small risks. Technical glyphosate (acid or salts) is of low to moderate toxicity; however, when mixed with some formulants such as polyoxyethylene amines (POEAs), toxicity to aquatic animals increases about 15-fold on average. However, glyphosate and the formulants have different fates in the environment and they do not necessarily co-occur. Therefore, toxicity tests on formulated products in scenarios where they would not be used are unrealistic and of limited use for assessment of risk. Concentrations of glyphosate in surface water are generally low with minimal risk to aquatic organisms, including plants. Toxicity and risks to non-target terrestrial organisms other than plants treated directly are low and risks to terrestrial invertebrates and microbial processes in soil are very small. Formulations containing POEAs are not labeled for use over water but, because POEA rapidly partitions into sediment, risks to aquatic organisms from accidental over-sprays are reduced in shallow water bodies. We conclude that use of formulations of glyphosate under good agricultural practices presents a de minimis risk of direct and indirect adverse effects in non-target organisms.

Effects of atrazine on fish, amphibians, and reptiles: update of the analysis based on quantitative weight of evidence.

Quantitative weight of evidence (QWoE) provides a framework and process for evaluating different toxicological studies based on quality and relevance of the results. This framework allows for data from these studies to be combined in separate lines of evidence to address causality, and relevance to environmental risks. In 2014, such a QWoE that examined the body of available company reports and peer reviewed literature regarding the effects of the herbicide atrazine on fish, amphibians, and reptiles was published. Since that time, new studies have been conducted and/or published. One of the advantages of the QWoE framework is that additional information can be added as it becomes available. Thus, these new studies were evaluated in the same manner as previously and the new data incorporated into the existing QWoE. As before, the new updated QWoE was based on the same process of objective scoring of individual studies with respect to the quality of the methods and the relevance of individual responses to the apical endpoints of survival, growth, development, and reproduction. These new data did not identify new responses or indicate any relevant effects of atrazine. The new updated QWoE analysis concluded that atrazine does not adversely affect fish, amphibians, and reptiles, at environmentally relevant concentrations (<100 µg atrazine/L), which is consistent with the previous conclusions. These new studies and data are discussed in this paper and the accompanying supplement information provides detailed and transparent information to support these conclusions.

Impact of 5α-reductase inhibitor and α-blocker therapy for benign prostatic hyperplasia on prostate cancer incidence and mortality.

OBJECTIVE: To investigate the use of 5α-reductase inhibitors (5ARIs) and α-blockers among men with benign prostatic hyperplasia (BPH) in relation to prostate cancer (PCa) incidence, severity and mortality. PATIENTS AND METHODS: A retrospective 20-year cohort study in men residing in Saskatchewan, aged 40-89 years, with a BPH-coded medical claim between 1995 and 2014, was conducted. Cox proportional hazards regression was used to compare incidence of PCa diagnosis, metastatic PCa, Gleason score 8-10 PCa, and PCa mortality among 5ARI users (n = 4 571), α-blocker users (n = 7 764) and non-users (n = 11 677). RESULTS: In comparison with both non-users and α-blocker users, 5ARI users had a ~40% lower risk of a PCa diagnosis (11.0% and 11.4% vs 5.8%, respectively), and α-blocker users had an 11% lower risk of a PCa diagnosis compared with non-users. Overall, the incidence of metastatic PCa and PCa mortality was not significantly different among 5ARI or α-blocker users compared with non-users (adjusted hazard ratios [HR] of metastatic PCa: 1.12 and 1.13, respectively, and PCa mortality: 1.11 and 1.18, respectively, P > 0.05 for both drugs), but both 5ARI and a-blocker users had ~30% higher risk of Gleason score 8-10 cancer, adjusted HR 1.37, 95% confidence interval [CI] 1.03-1.82, P = 0.03, and adjusted HR 1.28, 95% CI 1.03-1.59, P = 0.02, respectively compared with non-users. CONCLUSION: The use of 5ARIs was associated with lower risk of PCa diagnosis, regardless of comparison group. Risk of high grade PCa was higher among both 5ARI users and α-blocker users compared with non-users; however, this did not translate into higher risk of PCa mortality.

Response to Tennekes (2018) "The Resilience of the Beehive" Journal of Toxicology and Environmental Health B 20: 316-386.

This paper is a response to a letter from Dr. H Tennekes ("The Resilience of the Beehive" Journal of Toxicology and Environmental Health B 20: 316-386). Here we emphasize that our quantitative weight of evidence analyses were focused on the level of the honeybee colony. These colony-level responses include redundancy and resiliency as well as a number of possible sublethal effects of pesticides on the colony. We also note that the literature has shown that binding of neonicotinoid insecticides to the nicotinic acetylcholine receptor is reversible. The comments in this letter do not provide reasons to change our conclusions, that, as currently used in good agricultural practices as seed-treatments, imidacloprid, clothianidin, and thiamethoxam do not present significant risks to honeybees at the level of the colony.

Bioaccumulation of Polybrominated Diphenyl Ethers and Alternative Halogenated Flame Retardants in a Vegetation-Caribou-Wolf Food Chain of the Canadian Arctic.

The trophodynamics of halogenated flame retardants (HFRs) including polybrominated diphenyl ethers (PBDEs) and alternative HFRs were investigated in the terrestrial, vegetation-caribou-wolf food chain in the Bathurst Region of northern Canada. The greatest concentrations in vegetation (geometric mean of lichens, moss, grasses, willow, and mushrooms) were of the order 2,4,6-tribromophenyl allyl ether (TBP-AE) (10 ng g-1 lw) > BDE47 (5.5 ng g-1 lw) > BDE99 (3.9 ng g-1 lw) > BDE100 (0.82 ng g-1 lw) > 1,2,3,4,5-pentabromobenzene (PBBz) (0.72 ng g-1 lw). Bioconcentration among types of vegetation was consistent, though it was typically greatest in rootless vegetation (lichens, moss). Biomagnification was limited in mammals; only BDE197, BDE206-208 and ∑PBDE biomagnified to caribou from vegetation [biomagnification factors (BMFs) = 2.0-5.1]. Wolves biomagnified BDE28/33, BDE153, BDE154, BDE206, BDE207, and ∑PBDE significantly from caribou (BMFs = 2.9-17) but neither mammal biomagnified any alternative HFRs. Only concentrations of BDE28/33, BDE198, nonaBDEs, and ∑PBDE increased with trophic level, though the magnitude of biomagnification was low relative to legacy, recalcitrant organochlorine contaminants [trophic magnification factors (TMFs) = 1.3-1.8]. Despite bioaccumulation in vegetation and mammals, the contaminants investigated here exhibited limited biomagnification potential and remained at low parts per billion concentrations in wolves.

Evidence for Feedback Regulation Following Cholesterol Lowering Therapy in a Prostate Cancer Xenograft Model.

BACKGROUND: Epidemiologic data suggest cholesterol-lowering drugs may prevent the progression of prostate cancer, but not the incidence of the disease. However, the association of combination therapy in cholesterol reduction on prostate or any cancer is unclear. In this study, we compared the effects of the cholesterol lowering drugs simvastatin and ezetimibe alone or in combination on the growth of LAPC-4 prostate cancer in vivo xenografts. METHODS: Proliferation assays were conducted by MTS solution and assessed by Student's t-test. 90 male nude mice were placed on a high-cholesterol Western-diet for 7 days then injected subcutaneously with 1 × 105 LAPC-4 cells. Two weeks post-injection, mice were randomized to control, 11 mg/kg/day simvastatin, 30 mg/kg ezetimibe, or the combination and sacrificed 42 days post-randomization. We used a generalized linear model with the predictor variables of treatment, time, and treatment by time (i.e., interaction term) with tumor volume as the outcome variable. Total serum and tumor cholesterol were measured. Tumoral RNA was extracted and cDNA synthesized from 1 ug of total RNA for quantitative real-time PCR. RESULTS: Simvastatin directly reduced in vitro prostate cell proliferation in a dose-dependent, cell line-specific manner, but ezetimibe had no effect. In vivo, low continuous dosing of ezetimibe, delivered by food, or simvastatin, delivered via an osmotic pump had no effect on tumor growth compared to control mice. In contrast, dual treatment of simvastatin and ezetimibe accelerated tumor growth. Ezetimibe significantly lowered serum cholesterol by 15%, while simvastatin had no effect. Ezetimibe treatment resulted in higher tumor cholesterol. A sixfold induction of low density lipoprotein receptor mRNA was observed in ezetimibe and the combination with simvastatin versus control tumors. CONCLUSIONS: Systemic cholesterol lowering by ezetimibe did not slow tumor growth, nor did the cholesterol independent effects of simvastatin and the combined treatment increased tumor growth. Despite lower serum cholesterol, tumors from ezetimibe treated mice had higher levels of cholesterol. This study suggests that induction of low density lipoprotein receptor is a possible mechanism of resistance that prostate tumors use to counteract the therapeutic effects of lowering serum cholesterol. Prostate 77:446-457, 2017. © 2016 Wiley Periodicals, Inc.

A framework for cumulative risk assessment in the 21st century.

The ILSI Health and Environmental Sciences Institute (HESI) has developed a framework to support a transition in the way in which information for chemical risk assessment is obtained and used (RISK21). The approach is based on detailed problem formulation, where exposure drives the data acquisition process in order to enable informed decision-making on human health safety as soon as sufficient evidence is available. Information is evaluated in a transparent and consistent way with the aim of optimizing available resources. In the context of risk assessment, cumulative risk assessment (CRA) poses additional problems and questions that can be addressed using the RISK21 approach. The focus in CRA to date has generally been on chemicals that have common mechanisms of action. Recently, concern has also been expressed about chemicals acting on multiple pathways that lead to a common health outcome, and non-chemical other conditions (non-chemical stressors) that can lead to or modify a common outcome. Acknowledging that CRAs, as described above, are more conceptually, methodologically and computationally complex than traditional single-stressor risk assessments, RISK21 further developed the framework for implementation of workable processes and procedures for conducting assessments of combined effects from exposure to multiple chemicals and non-chemical stressors. As part of the problem formulation process, this evidence-based framework allows the identification of the circumstances in which it is appropriate to conduct a CRA for a group of compounds. A tiered approach is then proposed, where additional chemical stressors and/or non-chemical modulating factors (ModFs) are considered sequentially. Criteria are provided to facilitate the decision on whether or not to include ModFs in the formal quantitative assessment, with the intention to help focus the use of available resources to have the greatest potential to protect public health.

Quantitative weight of evidence assessment of higher tier studies on the toxicity and risks of neonicotinoids in honeybees. 3. Clothianidin.

A quantitative weight of evidence (QWoE) methodology was used to assess higher tier studies on the effects of clothianidin (CTD) on honeybees. Assessment endpoints were population size and viability of commercially managed bees and quantity of hive products. A colony-level no-observed-adverse effect concentration (NOAEC) of 25 µg CTD/kg syrup, equivalent to an oral no-observed-adverse effect-dose (NOAED) of 7.3 ng/bee/d for all responses measured. Based on a NOAEC of 19.7 µg/kg pollen, the NOAED for honeybee larvae was 2.4 ng/bee larva/d. For exposures via dust, a no-observed-adverse effect rate of 4 g CTD/ha was used to assess relevance of exposures via deposition of dust. The overall weight of evidence suggested that there is minimal risk to honeybees from exposure to CTD from its use as a seed treatment. For exposures via dust, dust/seed and dust/foliar applications, there were no exposures greater than the NOAED for CTD in nectar and pollen, indicating a de minimis risk to honeybees when the route of exposure was via uptake in plants. Analysis of effect studies in the field indicated a consistent lack of relevant effects, regardless of the way CTD was applied. For exposures via dust, there were no adverse effects because of these applications and there were no exposures greater than the NOAED for CTD in nectar and pollen. The overall weight of evidence based on many studies indicated no adverse effects on colony viability or survival of the colony. Thus, the overall conclusion is that clothianidin, as currently used in good agricultural practices, does not present a significant risk to honeybees at the level of the colony.

Quantitative weight of evidence assessment of higher-tier studies on the toxicity and risks of neonicotinoids in honeybees. 2. Imidacloprid.

A quantitative weight of evidence (QWoE) methodology was used to assess higher-tier studies on the effects of imidacloprid (IMI) on honeybees. Assessment endpoints were population size and viability of commercially managed bees and quantity of hive products. A colony-level no-observed-adverse effect concentration (NOAEC) of 25 µg IMI/kg syrup, equivalent to an oral no-observed-adverse-effect-dose of 7.3 ng/bee/d for all responses, was measured. The overall weight of evidence indicates that there is minimal risk to honeybees from exposure to IMI from its use as a seed treatment. Exposures via dusts from currently used seed coatings present a de minimis risk to honeybees when the route of exposure is via uptake in plants that are a source of pollen or nectar for honeybees. There were few higher-tier observational (ecoepidemiological) studies conducted with IMI. Considering all lines of evidence, the quality of the studies included in this analysis was variable, but the results of the studies were consistent and point to the same conclusion - that IMI had no adverse effects on viability of the honeybee colony. Thus, the overall conclusion is that IMI, as currently used as a seed treatment and with good agricultural practices, does not present a significant risk to honeybees at the level of the colony.

Quantitative weight of evidence assessment of risk to honeybee colonies from use of imidacloprid, clothianidin, and thiamethoxam as seed treatments: a postscript.

This paper is a postscript to the four companion papers in this issue of the Journal (Solomon and Stephenson 2017a , 2017b ; Stephenson and Solomon 2017a , 2017b ). The first paper in the series described the conceptual model and the methods of the QWoE process. The other three papers described the application of the QWoE process to studies on imidacloprid (IMI), clothianidin (CTD), and thiamethoxam (TMX). This postscript was written to summarize the utility of the methods used in the quantitative weight of evidence (QWoE), the overall relevance of the results, and the environmental implications of the findings. Hopefully, this will be helpful to others who wish to conduct QWoEs and use these methods in assessment of risks.

Quantitative weight of evidence assessment of higher tier studies on the toxicity and risks of neonicotinoids in honeybees. 4. Thiamethoxam.

A quantitative weight of evidence (QWoE) methodology was used to assess several higher-tier studies on the effects of thiamethoxam (TMX) on honeybees. Assessment endpoints were population size and viability of commercially managed honeybee colonies and quantity of hive products. A higher-tier field toxicology study indicated a no-observed-adverse effect concentration (NOAEC) of 29.5 µg TMX/kg syrup, equivalent to an oral no-observed-adverse-effect-dose (NOAED) of 8.6 ng/bee/day for all responses measured. For exposures via deposition of dust, a conservative no-observed-adverse-effect-rate at the level of the colony was 0.1 g TMX/ha. There was minimal risk to honeybees from exposure to TMX via nectar and pollen from its use as a seed-treatment. For exposures via dust and dust/seed applications, there were no concentrations above the risk values for TMX in nectar and pollen. Although some risks were identified for potential exposures via guttation fluid, this route of exposure is incomplete; no apparent adverse effects were observed in field studies. For exposures via dust/seed and dust/foliar applications, few adverse effects were observed. Considering all lines of evidence, the quality of the studies included in this analysis was variable. However, the results of the studies were consistent and point to the same conclusion. The overall weight of evidence based on many studies indicates that TMX has no adverse effects on viability or survival of the colony. Thus, the overall conclusion is that the treatment of seeds with thiamethoxam, as currently used in good agricultural practices, does not present a significant risk to honeybees at the level of the colony.

Quantitative weight of evidence assessment of higher-tier studies on the toxicity and risks of neonicotinoid insecticides in honeybees 1: Methods.

A quantitative weight of evidence (QWoE) methodology was developed and used to assess many higher-tier studies on the effects of three neonicotinoid insecticides: clothianidin (CTD), imidacloprid (IMI), and thiamethoxam (TMX) on honeybees. A general problem formulation, a conceptual model for exposures of honeybees, and an analysis plan were developed. A QWoE methodology was used to characterize the quality of the available studies from the literature and unpublished reports of studies conducted by or for the registrants. These higher-tier studies focused on the exposures of honeybees to neonicotinoids via several matrices as measured in the field as well as the effects in experimentally controlled field studies. Reports provided by Bayer Crop Protection and Syngenta Crop Protection and papers from the open literature were assessed in detail, using predefined criteria for quality and relevance to develop scores (on a relative scale of 0-4) to separate the higher-quality from lower-quality studies and those relevant from less-relevant results. The scores from the QWoEs were summarized graphically to illustrate the overall quality of the studies and their relevance. Through mean and standard errors, this method provided graphical and numerical indications of the quality and relevance of the responses observed in the studies and the uncertainty associated with these two metrics. All analyses were conducted transparently and the derivations of the scores were fully documented. The results of these analyses are presented in three companion papers and the QWoE analyses for each insecticide are presented in detailed supplemental information (SI) in these papers.

Critical assessment of pendimethalin in terms of persistence, bioaccumulation, toxicity, and potential for long-range transport.

Pendimethalin (PND, CAS registry number 40487-42-1) is a dinitroaniline herbicide that selectively controls broad-leaf and grassy weeds in a variety of crops and in noncrop areas. It has been on the market for about 30 yr and is currently under review for properties related to persistence (P), bioaccumulation (B), and toxicity (T) in the European Union (EU). A critical review of these properties as well as potential for long-range transport (LRT) was conducted. Pendimethalin has a geometric mean (GM) half-life of 76-98 d in agriculturally relevant soils under aerobic conditions in the lab. The anaerobic half-life was 12 d. The GM for field half-lives was 72 d. The GM half-life for sediment-water tests in the lab was 20 d and that in field aquatic cosms ranged from 45 to 90 d. From these data PND is not persistent as defined in the Annex II of EC regulation 1107/2009. The GM bioconcentration factor for PND was 1878, less than the criterion value. This was consistent with lack of biomagnification or accumulation in aquatic and terrestrial food chains. The GM no-observed-effect concentration (NOEC) value for fish was 43 µg/L, and 11 µg/L for algae. These do not trigger the criterion value for toxicity. In air, the DT50 of PND was estimated to be 0.35 d, which is well below the criterion of 2 d for LRT under the United Nations Economic Commission for Europe (UNECE) Aarhus protocol. Modeling confirmed lack of LRT. Because of its volatility, PND may be transported over short distances in air and was found in samples in local and semiremote regions; however, these concentrations are not of toxicological concern. Unlike other current-use pesticides, PND has not been found in samples from remote regions since 2000 and there is no apparent evidence that this herbicide accumulates in food chains in the Arctic.

Glyphosate in the general population and in applicators: a critical review of studies on exposures.

The recent classification of glyphosate as a probable human carcinogen by the International Agency for Research on Cancer (IARC) was arrived at without a detailed assessment of exposure. Glyphosate is widely used as an herbicide, which might result in exposures of the general public and applicators. Exposures were estimated from information in the open literature and unpublished reports provided by Monsanto Company. Based on the maximum measured concentration in air, an exposure dose of 1.04 × 10 - 6 mg/kg body mass (b.m.)/d was estimated. Assuming consumption of surface water without treatment, the 90th centile measured concentration would result in a consumed dose of 2.25 × 10 - 5 mg/kg b.m./d. Estimates by the Food and Agriculture Organization of the United Nations (FAO) of consumed doses in food provided a median exposure of 0.005 mg/kg b.m./d (range 0.002-0.013). Based on tolerance levels, the conservative estimate by the US Environmental Protection Agency (US EPA) for exposure of the general population via food and water was 0.088 mg/kg b.m./d (range 0.058-0.23). For applicators, 90th centiles for systemic exposures based on biomonitoring and dosimetry (normalized for penetration through the skin) were 0.0014 and 0.021 mg/kg b.m./d, respectively. All of these exposures are less than the reference dose and the acceptable daily intakes proposed by several regulatory agencies, thus supporting a conclusion that even for these highly exposed populations the exposures were within regulatory limits.

Problem formulation for risk assessment of combined exposures to chemicals and other stressors in humans.

When the human health risk assessment/risk management paradigm was developed, it did not explicitly include a "problem formulation" phase. The concept of problem formulation was first introduced in the context of ecological risk assessment (ERA) for the pragmatic reason to constrain and focus ERAs on the key questions. However, this need also exists for human health risk assessment, particularly for cumulative risk assessment (CRA), because of its complexity. CRA encompasses the combined threats to health from exposure via all relevant routes to multiple stressors, including biological, chemical, physical and psychosocial stressors. As part of the HESI Risk Assessment in the 21st Century (RISK21) Project, a framework for CRA was developed in which problem formulation plays a critical role. The focus of this effort is primarily on a chemical CRA (i.e., two or more chemicals) with subsequent consideration of non-chemical stressors, defined as "modulating factors" (ModFs). Problem formulation is a systematic approach that identifies all factors critical to a specific risk assessment and considers the purpose of the assessment, scope and depth of the necessary analysis, analytical approach, available resources and outcomes, and overall risk management goal. There are numerous considerations that are specific to multiple stressors, and proper problem formulation can help to focus a CRA to the key factors in order to optimize resources. As part of the problem formulation, conceptual models for exposures and responses can be developed that address these factors, such as temporal relationships between stressors and consideration of the appropriate ModFs.

A review of the carcinogenic potential of glyphosate by four independent expert panels and comparison to the IARC assessment.

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 non-Hodgkin'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.

Quantitative weight-of-evidence analysis of the persistence, bioaccumulation, toxicity, and potential for long-range transport of the cyclic volatile methyl siloxanes.

Cyclic volatile methyl siloxanes (cVMSs) are highly volatile and have an unusual combination of physicochemical properties, which are unlike those of halocarbon-based chemicals used to establish criteria for identification of persistent organic pollutants (POPs) that undergo long-range transport (LRT). A transparent quantitative weight of evidence (QWoE) evaluation was conducted to characterize their properties. Measurements of concentrations of cVMSs in the environment are challenging, but currently, concentrations measured in robust studies are all less than thresholds of toxicity. The cVMSs are moderately persistent in air with half-lives ≤11 d (greater than the criterion of 2 d) but these compounds partition into the atmosphere, the final sink. The cVMSs are rapidly degraded in dry soils, partition from wet soils into the atmosphere, and are not classifiable as persistent in soils. Persistence in water and sediment is variable, but the greatest concentrations in the environment are observed in sediments. Based upon the measurements that have been made in the environment, cVMSs should not be classified as persistent. Studies in food webs support a conclusion that the cVMSs do not biomagnify, a conclusion that is consistent with results of toxicokinetic studies. Concentrations in air in remote locations are small and deposition has not been detected. Taken together, evidence indicates that traditional measures of persistence and biomagnification used for legacy POP are not suitable for cVMS. Refined approaches used here suggest that cVMSs are not classifiable as persistent, bioaccumulative, or toxic. Further, these chemicals do not undergo LRT in the sense of legacy POPs.