Comparisons of PNEC derivation logic flows under example regulatory schemes and implications for ecoTTC.

Derivation of Predicted No Effect Concentrations (PNECs) for aquatic systems is the primary deterministic form of hazard extrapolation used in environmental risk assessment. Depending on the data availability, different regulatory jurisdictions apply application factors (AFs) to the most sensitive measured endpoint to derive the PNEC for a chemical. To assess differences in estimated PNEC values, two PNEC determination methodologies were applied to a curated public database using the EnviroTox Platform (www.EnviroToxdatabase.org). PNECs were derived for 3647 compounds using derivation procedures based on example US EPA and a modified European Union chemical registration procedure to allow for comparisons. Ranked probability distributions of PNEC values were developed and 5th percentile values were calculated for the entire dataset and scenarios where full acute or full chronic data sets were available. The lowest PNEC values indicated categorization based on chemical attributes and modes of action would lead to improved extrapolations. Full acute or chronic datasets gave measurably higher 5th percentile PNEC values. Algae were under-represented in available ecotoxicity data but drove PNECs disproportionately. Including algal inhibition studies will be important in understanding chemical hazards. The PNEC derivation logic flows are embedded in the EnviroTox Platform providing transparent and consistent PNEC derivations and PNEC distribution calculations.

The impact of sea ice conditions on breeding decisions is modulated by body condition in an arctic partial capital breeder.

Determining how environmental conditions interact with individual intrinsic properties is important for unravelling the underlying mechanisms that drive variation in reproductive decisions among migratory species. We investigated the influence of sea ice conditions and body condition at arrival on the breeding propensity, i.e. the decision to reproduce or not within a single breeding season, and timing of laying in migrating common eiders (Somateria mollissima) breeding in the Arctic. Using Radarsat satellite images acquired from 2002 to 2013, we estimated the proportion of open water in the intertidal zone in early summer to track the availability of potential foraging areas for pre-breeding females. Timing of ice-breakup varied by up to 20 days across years and showed strong relationship with both breeding propensity and the timing of laying of eiders: fewer pre-breeding individuals were resighted nesting in the colony and laying was also delayed in years with late ice-breakup. Interestingly, the effect of sea ice dynamics on reproduction was modulated by the state of individuals at arrival on the breeding grounds: females arriving in low condition were more affected by a late ice-breakup. Open water accessibility in early summer, a likely proxy of food availability, is thus crucial for reproductive decisions in a (partial) capital breeder. Our predictive capacity in determining how Arctic-breeding seabirds respond to changes in environmental conditions will require incorporating such cross-seasonal cumulative effects.

Mode of Action (MOA) Assignment Classifications for Ecotoxicology: An Evaluation of Approaches.

The mode of toxic action (MOA) is recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, MOA classification has never been standardized in ecotoxicology, and a comprehensive comparison of classification tools and approaches has never been reported. Here we critically evaluate three MOA classification methodologies using an aquatic toxicity data set of 3448 chemicals, compare the approaches, and assess utility and limitations in screening and early tier assessments. The comparisons focused on three commonly used tools: Verhaar prediction of toxicity MOA, the U.S. Environmental Protection Agency (EPA) ASsessment Tool for Evaluating Risk (ASTER) QSAR (quantitative structure activity relationship) application, and the EPA Mode of Action and Toxicity (MOAtox) database. Of the 3448 MOAs predicted using the Verhaar scheme, 1165 were classified by ASTER, and 802 were available in MOAtox. Of the subset of 432 chemicals with MOA assignments for each of the three schemes, 42% had complete concordance in MOA classification, and there was no agreement for 7% of the chemicals. The research shows the potential for large differences in MOA classification between the five broad groups of the Verhaar scheme and the more mechanism-based assignments of ASTER and MOAtox. Harmonization of classification schemes is needed to use MOA classification in chemical hazard and risk assessment more broadly.

Alternatives to in vivo tests to detect endocrine disrupting chemicals (EDCs) in fish and amphibians--screening for estrogen, androgen and thyroid hormone disruption.

Endocrine disruption is considered a highly relevant hazard for environmental risk assessment of chemicals, plant protection products, biocides and pharmaceuticals. Therefore, screening tests with a focus on interference with estrogen, androgen, and thyroid hormone pathways in fish and amphibians have been developed. However, they use a large number of animals and short-term alternatives to animal tests would be advantageous. Therefore, the status of alternative assays for endocrine disruption in fish and frogs was assessed by a detailed literature analysis. The aim was to (i) determine the strengths and limitations of alternative assays and (ii) present conclusions regarding chemical specificity, sensitivity, and correlation with in vivo data. Data from 1995 to present were collected related to the detection/testing of estrogen-, androgen-, and thyroid-active chemicals in the following test systems: cell lines, primary cells, fish/frog embryos, yeast and cell-free systems. The review shows that the majority of alternative assays measure effects directly mediated by receptor binding or resulting from interference with hormone synthesis. Other mechanisms were rarely analysed. A database was established and used for a quantitative and comparative analysis. For example, a high correlation was observed between cell-free ligand binding and cell-based reporter cell assays, between fish and frog estrogenic data and between fish embryo tests and in vivo reproductive effects. It was concluded that there is a need for a more systematic study of the predictive capacity of alternative tests and ways to reduce inter- and intra-assay variability.

Addressing moral injury in the military.

Moral injury is a relatively new, but increasingly studied, construct in the field of mental health, particularly in relation to current and ex-serving military personnel. Moral injury refers to the enduring psychosocial, spiritual or ethical harms that can result from exposure to high-stakes events that strongly clash with one's moral beliefs. There is a pressing need for further research to advance understanding of the nature of moral injury; its relationship to mental disorders such as posttraumatic stress disorder and depression; triggering events and underpinning mechanisms; and prevalence, prevention and treatment. In the meantime, military leaders have an immediate need for guidance on how moral injury should be addressed and, where possible, prevented. Such guidance should be theoretically sound, evidence-informed and ethically responsible. Further, the implementation of any practice change based on the guidance should contribute to the advancement of science through robust evaluation. This paper draws together current research on moral injury, best-practice approaches in the adjacent field of psychological resilience, and principles of effective implementation and evaluation. This research is combined with the military and veteran mental health expertise of the authors to provide guidance on the design, implementation and evaluation of moral injury interventions in the military. The paper discusses relevant training in military ethical practice, as well as the key roles leaders have in creating cohesive teams and having frank discussions about the moral and ethical challenges that military personnel face.

Assessment of the environmental risk of long-chain aliphatic alcohols.

An environmental assessment of long-chain alcohols (LCOH) has recently been conducted under the OECD SIDS High Production Volume (HPV) Program via the Global International Council of Chemical Associations (ICCA) Aliphatic Alcohols Consortium. LCOH are used primarily as intermediates, as a precursor to alcohol-based surfactants and as alcohol per se in a wide variety of consumer product applications. Global production volume is approximately 1.58 million metric tonnes. The OECD HPV assessment covers linear to slightly branched LCOH ranging from 6 to 22 alkyl carbons (C). LCOH biodegrade exceptionally rapidly in the environment (half-lives on the order of minutes); however, due to continuous use and distribution to wastewater treatment systems, partitioning properties, biodegradation of alcohol-based surfactants, and natural alcohol sources, LCOH are universally detected in wastewater effluents. An environmental risk assessment of LCOH is presented here by focusing on the most prevalent and toxic members of the linear alcohols, specifically, from C(12-15). The assessment includes environmental monitoring data for these chain lengths in final effluents of representative wastewater treatment plants and covers all uses of alcohol (i.e., the use of alcohol as a substance and as an intermediate for the manufacturing of alcohol-based surfactants). The 90th percentile effluent discharge concentration of 1.979microg/L (C(12)-C(15)) was determined for wastewater treatment plants in 7 countries. Chronic aquatic toxicity studies with Daphnia magna demonstrated that between C(13) and C(15) LCOH solubility became a factor and that the structure-activity relationship was characterized by a toxicity maximum between C(13) and C(14). Above C(14) the LCOH was less toxic and become un-testable due to insolubility. Risk quotients based on a toxic units (TU) approach were determined for various scenarios of exposure and effects extrapolation. The global average TU ranged from 0.048 to 0.467 depending on the scenario employed suggesting a low risk to the environment. The fact that environmental exposure calculations include large fractions of naturally derived alcohol from animal, plant, and microbially mediated biotransformations further supports a conclusion of low risk.

Environmental properties of long-chain alcohols. Part 2: Structure-activity relationship for chronic aquatic toxicity of long-chain alcohols.

Daphnia magna reproduction tests were performed with C(10), C(12), C(14) and C(15) alcohols to establish a structure-activity relationship of chronic effects of long-chain alcohols. The data generation involved substantial methodological efforts due to the exceptionally rapid biodegradability of the test substances and the need to test as close as possible to their water solubility limits. Test concentrations were determined by GC-MS before and after test solution renewal. Whereas apparent toxicity based on survival and reproduction increased with increasing C-chain lengths up to C(14), observations of toxicity to C(15) alcohol were not in line with lower chain lengths due to the lack of toxicity below the level of water solubility. When omitting C(15), the slope of most (Q)SARs approach -1, being consistent with the expectation of a non-polar narcotic mode of action. Further testing at higher chain lengths is not sensible due to progressively lower solubility, at remaining biodegradability. Effects on mortality and reproduction are not expected below the level of water solubility.

SSDs Revisited: Part I-A Framework for Sample Size Guidance on Species Sensitivity Distribution Analysis.

We propose a framework on sample size for species sensitivity distribution (SSD) analyses, with perspectives on Bayesian, frequentist, and even nonparametric approaches to estimation. The intent of a statistical sample size analysis is to ensure that the implementation of a statistical model will satisfy a minimum performance standard when relevant conditions are met. It requires that a statistical model be fully specified and that the means of measuring its performance as a function of sample size be detailed. Defining the model conditions under which sample size is calculated is often the most difficult, and important, aspect of sample size analysis because if the model is not representative, then the sample size analysis will provide incorrect guidance. Definitive guidance on sample size requires general agreement on representative models and their performance from stakeholders in important domains such as chemical safety assessments involving government regulators and industry; the present study provides an initial framework that could be used to this end in the future. In addition, our analysis provides immediate value for understanding how well current SSD analyses perform under a few basic models, sample sizes, and quantitative performance criteria. The results confirm that many analyses are adequately sized to estimate hazardous concentration percentile values (typically the 5th percentile for chemical hazard assessments). However, on the low end of sizes seen in common practice, hazardous concentration estimates can be more than 1 order of magnitude greater than the model-defined value. Environ Toxicol Chem 2019;38:1514-1525. © 2019 SETAC.

SSDs revisited: part II-practical considerations in the development and use of application factors applied to species sensitivity distributions.

Application factors are routinely applied in the extrapolation of laboratory aquatic toxicity data to ensure protection from exposure to chemicals in the natural environment. The magnitude of the application factor is both a scientific and a policy decision, but in any case, it should be rooted in scientific knowledge so as to not be arbitrary. Information-rich chemicals are often subjected to species sensitivity distribution (SSD) analysis to transparently describe certain aspects of assessment uncertainty and are normally subjected to much smaller application factors than screening information data sets. We describe a new set of tools useful to assess the quality of SSDs. Twenty-two data sets and 19 chemicals representing agrochemicals, biocides, surfactants, metals, and common wastewater contaminants were compiled to demonstrate how the tools can be used. "Add-one-in" and "leave-one-out" simulations were used to investigate SSD robustness and develop quantitative evidence for the use of application factors. Theoretical new toxicity data were identified for add-one-in simulations based on the expected probabilities necessary to lower the hazardous concentration to 5% of a species (HC5) by a factor of 2, 3, 5, or 10. Simulations demonstrate the basis for application factors in the range of 1 to 5 for well-studied chemicals with high-quality SSDs. Leave-one-out simulations identify the fact that the most influential values in the SSD come from the extremes of the sensitive and tolerant toxicity values. Mesocosm and field data consistently demonstrate that HC5s are conservative, further justifying the use of small application factors for high-quality SSDs. Environ Toxicol Chem 2019;38:1526-1541. © 2019 SETAC.

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome.

The mouse Ly49 and human killer cell immunoglobulin-like receptors (KIR) gene clusters encode activating and inhibitory class I MHC receptors on natural killer (NK) cells. A direct correlation between the presence of multiple activating KIR and various human autoimmune diseases including diabetes has been shown. Previous studies have implicated NK cell receptors in the development of diabetes in the non-obese diabetic (NOD) inbred mouse strain. To assess the contribution of Ly49 to NOD disease acceleration the Ly49 gene cluster of these mice was sequenced. Remarkably, the NOD Ly49 haplotype encodes the largest haplotype and the most functional activating Ly49 of any known mouse strain. These activating Ly49 include three Ly49p-related and two Ly49h-related genes. The NOD cluster contains large regions highly homologous to both C57BL/6 and 129 haplotypes, suggesting unequal crossing over as a mechanism of Ly49 haplotype evolution. Interestingly, the 129-like region has duplicated in the NOD genome. Thus, the NOD Ly49 cluster is a unique mix of elements seen in previously characterized Ly49 haplotypes resulting in a disproportionately large number of functional activating Ly49 genes. Finally, the functionality of activating Ly49 in NOD mice was confirmed in cytotoxicity assays.

Comparative cytotoxicity of C-1311 in colon cancer in vitro and in vivo using the hollow fiber assay.

The aim of this study was to investigate the antiproliferative effects of C-1311 (Symadex), a member of the imidazoacridinone family, in human colorectal cancer cells. In the in vitro screen, C-1311 led to the most prominent growth inhibition in HT29, HCT116, and COLO205 cell lines when compared to oxaliplatin, CPT-11, DFUR, 5-FU and capecitabine. The GI(50)values for C-1311 ranged from 0.12 to 0.83 microM and the TGI concentrations (resulting in total growth inhibition) were 6- to 13-fold lower than those of other agents. In the hollow fiber assay in vivo, C-1311 caused 77% growth inhibition of HT29 in the intraperitoneal site as compared to paclitaxel (17% growth inhibition). In the subcutaneous site, C-1311 produced 57% growth inhibition while paclitaxel showed no cell growth inhibition effects. This unique cytotoxicity profile of C-1311 warrants further investigation and supports its clinical development in colon cancer patients. Symadex (C-1311) is currently in phase 2 clinical trials.

Interleukin-1 expression during hyperoxic lung injury in the mouse.

An important component of the pathophysiologic response to hyperoxia (O2) is pulmonary inflammation, although the roles of specific inflammatory mediators during pulmonary O2 toxicity are not completely known. Interleukin-1 (IL-1) is an early inflammatory mediator and is sufficient to elicit many of the responses associated with acute injury. The IL-1 family comprises two bioactive proteins, IL-1alpha and IL-1beta, and their natural antagonist IL-1ra. Here we report studies of IL-1 regulation during hyperoxic lung injury in the adult mouse. When assayed by Northern blot, increases in IL-1beta mRNA were seen after 2 days of hyperoxia. In contrast, IL-1alpha mRNA was barely detectable before 4 days of hyperoxia. To further understand the cellular origin of IL-1beta expression in lungs, in situ hybridization and immunohistochemical analyses were performed. IL-1beta mRNA or protein was not detected in the lungs of unexposed animals. At 3 days, we observed the accumulation of IL-1beta transcripts in pulmonary interstitial macrophages and in a subset of neutrophils, and immunodetectable IL-1beta protein was co-localized in adjacent sections. At 4 days of exposure, IL-1beta transcripts were widespread in lung tissue, but many areas rich in IL-1beta mRNA were devoid of immunodetectable IL-1beta. However, it is not known whether increased synthesis of IL-1beta or the uncoupling of IL-1beta protein and mRNA accumulation has a role in pathophysiology of pulmonary O2 toxicity.

Expression of calcitonin gene-related peptide, substance P and protein kinase C in cultured dorsal root ganglion neurons following chronic exposure to mu, delta and kappa opiates.

The mechanisms involved in morphine tolerance are poorly understood. It was reported by our group that calcitonin gene-related peptide (CGRP)-like immunoreactivity (IR) was increased in the spinal dorsal horn during morphine tolerance [Ménard et al. (1996) J. Neurosci. 16, 2342-2351]. More recently, we observed that it was possible to mimic these results in cultured dorsal root ganglion (DRG) neurons allowing for more detailed mechanistic studies [Ma et al. (2000) Neuroscience 99, 529-539]. The aim of the present series of experiments was to further validate the DRG cell culture model by establishing which subtypes of opioid receptors are involved in the induction of CGRP in cultured rat DRG neurons, and to examine the signaling pathway possibly involved in the induction of CGRP-like IR following repeated opiate treatments. Other neuropeptides known to be expressed in DRG neurons, such as substance P (SP), neuropeptide Y (NPY) and galanin, were investigated to assess specificity. Following treatment with any of the three opioid agonists (mu, DAMGO; delta, DPDPE; kappa, U50488H), the number of CGRP- and SP-IR cultured DRG neurons increased significantly, and in a concentration-dependent manner, with the effects of kappa agonist being less pronounced. NPY and galanin were not affected.Double-immunofluorescence staining showed that the three opioid receptors were co-localized with both CGRP- and SP-like IR.Protein kinase C (PKC)-like IR was found to be significantly increased following a repetitive treatment with DAMGO. Double-immunofluorescence staining showed the co-localization of PKCalpha with CGRP- and SP-IR in cultured DRG neurons. Moreover, a combined treatment with DAMGO and a PKC inhibitor (chelerythrine chloride or Gö 6976) was able to block the effects of the opioid on increased CGRP-like IR. These data suggest that the three opioid receptors may be involved in the induction of CGRP and SP observed following chronic exposure to opiates, and that PKC probably plays a role in the signaling pathway leading to the up-regulation of these neuropeptides. These findings further validate the DRG cell culture as a suitable model to study intracellular pathways that govern changes seen following repeated opioid treatments possibly leading to opioid tolerance.

Effect of intradialytic parenteral nutrition on delivered Kt/V.

The purpose of the study is to determine the effect of intradialytic parenteral nutrition (IDPN) and its components on delivered Kt/V (Kt/Vd). Nineteen patients undergoing routine outpatient hemodialysis and receiving IDPN were enrolled onto this prospective, crossover study. To reduce the confounding of time, assigned treatment in the first week was random, with patient crossover in the fourth week. Patients served as their own controls. In the successive 6 weeks, patients received IDPN solutions differing in whether amino acids (AAs), dextrose, or lipids were included or excluded. The primary end point was Kt/Vd, measured with a single-pool, variable-volume urea kinetic model. Other factors with the potential to impact on Kt/Vd were controlled and/or monitored. The administration of IDPN with all three components resulted in a significantly reduced mean Kt/Vd. When patients received AA-containing solutions, mean Kt/Vd was significantly less than when IDPN was withheld. Administration of solutions without AA resulted in a mean Kt/Vd not significantly different from mean Kt/Vd when IDPN was withheld. The mean prescribed Kt/V did not differ from mean Kt/Vd when IDPN was withheld. Simulation analyses of increased urea generation (Gu) showed an increase in patient urea volume and decreased Kt/V similar to the study findings. AA-containing IDPN solutions resulted in a significant reduction in Kt/Vd, possibly mediated by increased Gu. Administration of IDPN solutions may have important clinical and economic consequences that warrant further investigation.

Chromal focus of acquired chromatic discrimination loss and solvent exposure among printshop workers.

Acquired dyschromatopsia has been associated with exposure to organic solvents. However, the chromal focus of the loss may be indicative of its gravity. According to Kollner's rule, blue-yellow loss reflects changes in external retinal layers, while red-green loss appears to be indicative of internal retinal or optic nerve damage. The objective of the present study was to examine chromatic discrimination capacity of 30 printshop workers exposed to organic solvent mixtures, and of a non-exposed reference group. Colour vision was assessed with a colour arrangement test designed to detect acquired dyschromatopsia, the Lanthony D-15 desaturated panel. Quantitative analysis, using Bowman's colour confusion index, revealed significantly higher scores indicative of colour vision loss among the exposed workers as compared to the non-exposed. Analysis of covariance, with age as co-variate, showed colour confusion index to be significantly associated with job category. Similarly, qualitative analysis showed that the exposed workers presented a significantly higher prevalence of acquired dyschromatopsia as compared to the non-exposed group. However, analysis of the type of chromatic discrimination loss showed that among the nonexposed persons, dyschromatopsia was localized only in the blue-yellow range, while for 35% of the dyschromatopic-exposed persons, red-green loss as well as blue-yellow loss were present. Three-dimensional chi 2-analysis showed that the complex pattern of dyschromatopsia was not related to age, but to job category. These findings suggest that the type of dyschromatopsia, reflecting the gravity of neural alterations, may be a function of exposure level and/or the ophthalmotoxic properties of the particular solvents used.

Antagonist of N-methyl-D-aspartate receptors partially prevent the development of cocaine sensitization.

Behavioral sensitization to cocaine was tested for in rats pretreated with MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, or D-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (D-CPPene), a competitive NMDA antagonist. A 5-day regimen of once-daily cocaine (15 mg/kg) injections yielded sensitization to cocaine (15 mg/kg)-induced behavioral activation. Cocaine sensitization was partially prevented by MK-801 (0.25 mg/kg) or D-CPPene (20 mg/kg) pretreatment. These results differ from previous reports that NMDA receptor antagonists completely prevented the development of stimulant sensitization. While raising questions about methodological differences among laboratories studying this issue, our findings suggest that sensitization may involve mechanisms dependent on NMDA-receptor function as well as NMDA receptor-independent mechanisms.

Pilot study of peripheral markers of catecholaminergic systems among workers occupationally exposed to toluene.

In a pilot study, serum dopamine beta-hydroxylase (DBH), platelets monoamine oxidase type B (MAO B) activities and basal plasma prolactin (PRL) were measured, among 10 workers occupationally exposed to toluene and 10 control subjects, preceding and immediately following vacation. Six exposed subjects were employed in an adhesive tape making industry and 4 in a paint making industry. Their median basal levels of urinary hippuric acid were 0.44 mmole/mmole creatinine (cr) (range 0.23-1.97) and 0.18 mmole/mmole cr (range 0.15-0.19) respectively, the second to last morning of the work week, preceding vacation. The level of basal urinary hippuric acid among the control group was 0.26 mmole/mmole cr (range 0.03-0.38). The workers from the adhesive tape plant reported a significantly higher number of symptoms experienced frequently (Kruskal, Wallis, p < 0.05). On a group basis, serum DBH was lowest among the workers from the adhesive tape plant, who had the highest levels of basal urinary hippuric acid. In addition, a negative relation was observed between hippuric acid and serum DBH, preceding and following vacation (Rho = -0.46, p = 0.05; Rho = -0.51, p = 0.03). The observed changes in serum DBH activity are consistent with its decrease in human, following long-term exposure to styrene, another aromatic hydrocarbon. The findings of this pilot study, on a limited number of individuals suggest that DBH may be a sensitive peripheral bioindicator. Further studies of larger groups should be done to confirm the decrease in serum DBH activity with toluene exposure and explore whether this alteration is related to the neurotoxic impairments associated with exposure.

Surveillance of early neurotoxic dysfunction.

Surveillance of early neurotoxic alterations was undertaken in 3 reinforced plastics plants, with a view to preventive intervention. Using a longitudinal study design, exposure parameters (environmental styrene in the respiratory zone of each worker and end-shift mandelic acid (MA)) and neurobehavioral performance (Neurobehavioral Core Test Battery and Field Assessment: Sensory Tests), were assessed at time zero (T0); recommendations were made to reduce exposure at jobsites with the highest risk. Reassessment was made two years later (T2). Complete exposure data was available for 118 workers at T0; 75 were still employed at T2; of these, 57 (76%) returned for testing. Those who returned had more seniority (p < 0.001) and higher MA (p < 0.01) and styrene (p < 0.05) levels at T0 than the others. Analyses, performed on the T0-T2 differences, showed improvement in exposure parameters in Plant 3, where lower levels were observed at T2 for styrene (p < 0.05) and MA (p < 0.001). workers in Plant 3 (n = 29) performed better (p < 0.05) at T2 for short term memory, perceptuo-motor speed, motor precision and manual dexterity; they reported more vigor (p < 0.05) and less anger (p = 0.07). This was not the case for the workers from the other plants. Generally, the T0-T2 difference in MA was associated (Spearman's Rho) with differences in color vision (p < 0.001), simple reaction time (mean and standard deviation), digit span forward, tension, fatigue and the number of symptoms (p < 0.05); aiming precision showed a similar tendency (p < 0.10). These findings suggest that group surveillance of early nervous system changes for jobs with exposure to neurotoxins, using a sensitive neurofunctional test battery, may be useful for preventive intervention.

Bioindicator and exposure data for a population based study of manganese.

Exposure data and bioindicators were obtained for a study whose objective was detection of early manifestations of manganese (Mn) neurotoxicity in a population with potential environmental exposure. The study included persons with no history of neurotoxic workplace exposure in Southwest Quebec, drawn from seven postal code regions, defining a set of geographically contiguous zones. Blood samples were analyzed for total Mn (MnB), lead (PbB), total mercury (HgT) and serum iron (FeS). Drinking water samples from participants' residences were analyzed for manganese (MnW). At 4 sites, limited 24-hour high volume air samples for total particulates (TP) and PM10, were analyzed for Mn and Pb. Sociodemographic and dietary information was obtained by self-administered questionnaire. The geometric mean (GM) for MnB values (n = 297) was 7.14 micrograms/L. Levels of MnB in women (n = 156; GM 7.50 micrograms/L) were significantly higher than in men (n = 141; GM 6.75 micrograms/L). No relationship was found between MnB and PbB or HgT. FeS was significantly higher in men (GM 18.38 mumol/L) than women (GM 15.0 mumol/L). For women, MnB was correlated to FeS, with a tendency to decrease with increasing age. For men, no relationship was found between MnB levels and either FeS or age, although FeS showed a strong inverse relationship with age. The 24-hour mean levels of MnTP at the 4 sites varied between 0.009 microgram/m3 and 0.035 microgram/m3; intersite differences were not significant. For Mn in PM10 (MnPM10), mean values ranged from 0.007 microgram/m3 to 0.019 microgram/m3; intersite differences were significant. A total of 278 MnW samples were obtained, 16 from residences served by wells. The GM for MnW was 4.11 micrograms/L (range: 0.50-71.1 micrograms/L, excluding wells; MnW for wells ranged from non-detectable to 158.9 micrograms/L. Individually, there was no relation between MnW and MnB. Geographic analysis of the MnB and MnW data by an algorithm grouping contiguous postal code zones, combined with air data, lead to definition of a geographic parameter, distinguishing two regions relative to a former manganese alloy plant, which contributed significantly to MnB. A multiple regression model was developed, explaining 6.7% of the variability in MnB (F = 5.12; p < 0.001); when controlling for gender, geographic region with higher levels of airborne manganese and the frequency of consumption of cereals and leaf vegetables contributed positively to MnB levels, while serum iron was negatively related.