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

<p>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 Exposures were estimated from information in the open literature and unpublished reports provided by Monsanto Company.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 ⁻ ⁶mg/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 ⁻ ⁵mg/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 <i>via</i> 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.</p

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

<p>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.</p

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

<p>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 <i>de minimis</i> 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.</p

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

<p>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.</p

Growth of LNCaP xenograft tumors in relation to serum cholesterol levels.

<p>Mean tumor weight (<b>A</b>) and volume (<b>B</b>) (with standard deviation and range) in mice with cholesterol levels above or below the median serum cholesterol level. P values from unpaired two sample t-tests. Mean tumor weight (<b>C</b>) and volume (<b>D</b>) (with standard deviation and range) in mice grouped by quartile of serum cholesterol levels. P values from one way ANOVA of mean values in the four quartiles, with a post test for linear trend. The mean cholesterol levels in tumors above or below the median, or in each quartile of cholesterol, and the number of mice in each group, are indicated below the x-axis in each graph.</p

Correlation of serum cholesterol levels with tumor weight, tumors androgens and expression of CYP17A in LNCaP xenografts.

<p>The correlation of serum cholesterol levels with tumor weight (<b>A</b>), testosterone (<b>B</b>) and DHT (<b>C</b>) in aggregated tumors from all four treatment cohorts (n = 52). Tumor androgens were determined by mass spectrometry. Correlation coefficients and p values from linear regression analysis.</p

Expression of steroidogenic enzymes necessary for <i>de novo</i> synthesis of androgens from cholesterol in LNCaP xenografts.

<p>(<b>A</b>) Enzymes and intermediates in the steroid bio-synthetic pathway leading from cholesterol to the formation of testosterone and DHT. LDLR and SR-B1 mediate cholesterol uptake; STAR and STARD3 mediate transport of cholesterol across the mitochondrial membrane where steroidogenesis is initiated. CYB5A is an important cofactor for the lyase activity of CYP17A. (<b>B</b>) Transcript profiling of tumors from all 4 treatment groups by qRT-PCR for the androgen receptor (AR), the androgen regulate gene PSA, and genes involved in cholesterol transport. (<b>C</b>) Transcript profiling for the expression of steroidogenic genes and the CYB5 cofactor. The mean cycle threshold (CT) for detection of each transcript was normalized to expression of the housekeeping gene RPL13A in the same sample (delta or dCT). (<b>D</b>) The correlation of serum cholesterol levels with transcript expression of CYP17A as measured by qRT-PCR. Correlation coefficients and p values from linear regression analysis.</p

Serum cholesterol and testosterone levels in murine cohorts receiving cholesterol targeted treatment.

<p>(<b>A</b>) Mean cholesterol levels (with standard deviation and range) in mice randomized to 12 weeks of treatment with the indicated combinations of a low fat/no cholesterol diet (LFNC) or high fat/high cholesterol diet (HFHC) ± ezetimibe (drug). One way ANOVA with a post test for linear trend was used to compare values in the four treatment groups. P values<0.05 were considered significant. (<b>B</b>) Measurement of serum testosterone levels by ELISA in mice receiving the indicated HFHC or LFNC diet (n = 10/group). Data are presented as testosterone (T) levels (ng/ml) vs. diet group ± SE. Differences between mice fed the two diets were not statistically significant (unpaired two sample t-test).</p

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

Network modeling of the cholesterol-responsive genes.

<p>(<b>A</b>) <b>A provisional network was generated from integration of two microarray data sets.</b> Node color represents increases (red), no significant changes (yellow), and decreases (green) in gene expression in murine prostate tissue after cholesterol alteration as ascertained by cDNA microarray. Changes in RNA expression levels of the corresponding nodes in LNCaP cells are shown as colored node boundaries (donut shape) and the color represents increases (red), no significant change (yellow), and decreases (green) in gene expression under CDM conditions compared to control. Arrows indicate direct activation, T-shaped lines direct repression, dashed arrows indirect activation, and lines physical interaction. (<b>B</b>) <b>Gene expression under Normo and Hyper conditions (</b><b><i>in vivo</i></b><b>).</b> To verify <i>in vivo</i> microarray data obtained from SCID experiments, mRNA levels of the indicated genes were determined. GAPDH expression was used to normalize gene expression. Error bars represent SD (n = 3). (<b>C</b>) <b>Gene expression under Control and Cholesterol-depleted conditions (</b><b><i>in vitro</i></b><b>).</b> LNCaP cells were incubated in CDM for 0, 3 or 16 h, and mRNA levels of the indicated genes were measured by RT-PCR analysis to validate cDNA microarray data. Error bars represent SD (n = 3). *<i>p</i><0.05 (Student’s t-test).</p