Adverse effects of pollution on mental health: the … effects of pollution on mental health: ... the sexual steroids pathway. Conse- ... particularly fish and marine

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For citation purposes: Lanoix D, Plusquellec P. Adverse effects of pollution on mental health: the stress hypothesis. OA Evidence-Based Medicine 2013 May 01;1(1):6.

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Adverse effects of pollution on mental health: the stress hypothesis

D Lanoix1, P Plusquellec1,2*

Glucocorticoids are able to cross the blood–brain barrier and reach the central structure involved in cognitive functions and emotional/behavioural regulation. Furthermore, studies have revealed that environ-mental contaminants significantly influence the stress system across a variety of wildlife animals, labora-tory animals and recently in humans. Conclusion The hypothesis of the stress system, linking environmental contaminant exposure to adverse mental health effects, needs to be addressed in future research. In addition, in cases of environmental contaminants tox-icity, clinicians could recommend the testing of the hypothalamic–pituitary–adrenal axis functioning in order to prevent children and/or the elderly to develop impairments due to its alteration.

IntroductionToxic metals and persistent organic pollutants (POPs) are two classes of well-studied environmental con-taminants (ECs) that have been shown to impact physical and men-tal health. Since the 1970s, regula-tory actions have been successfully implemented to reduce human expo-sure to these toxins. Recent studies have shown that toxic metals and POPs act at a very low level of expo-sure on physical and mental health. The endocrine-disrupting properties of these contaminants may explain their adverse physical and mental health effects. In the emerging field of research on endocrine disrup-tors, studies have mainly focused on the sexual steroids pathway. Conse-quently, the corticosteroids pathway (i.e. the stress pathway) has been largely overlooked in explaining the

effects of ECs on mental health. This paper discusses the adverse effects of pollution on mental health.

DiscussionThe authors have referenced some of their own studies in this review. These referenced studies have been conducted in accordance with the Declaration of Helsinki (1964) and the protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed. All human subjects, in these referenced studies, gave informed consent to participate in these studies.

Environmental contaminantsHuman exposure to ECs is a well-known phenomenon. Toxic metals and POPs are two classes of well-studied toxic substances with adverse health effects. These contaminants are ubiquitous and bioaccumulable, and chronic exposure is frequent despite public regulation attempts to reduce the sources of exposure. Although everyone is at risk to envi-ronmental toxin exposure, children and elders are especially sensitive. In proportion to body weight, children have higher food, water and air con-sumption than adults. They are also more exposed through playground and higher hand-to-mouth behav-iour. Furthermore, the brain develop-mental process during childhood and adolescence creates windows of great vulnerability to environmental tox-ins, in which even minute exposures can produce devastating results. As for older adults, their bodies contain a lifetime’s worth of ECs, and the ageing brain has a reduced ability to compensate for impairment such as those coming from environmental

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AbstractIntroduction Environmental contaminants are ubiquitous. Among the most studied environmental contaminants, lead, mercury, polychlorinated biphe-nyls and pesticides have been found to impact mental health. In par-ticular, exposure to environmental contaminants has been related to executive functions and emotional/behavioural maladjustment in chil-dren, and cognitive variability in elders. We hypothesise that the association between environmen-tal contaminants and mental health, particularly in children and elders, could be explained by a disruption of the stress system.Discussion Environmental contaminants act at very low levels of exposure that are not reflected by high doses. There-fore, public regulation agencies are consistently reducing acceptable blood levels of exposure. For exam-ple, clinical management plans for children and elders at risk of toxicity are thus adapted to reflect the novel blood lead action level. Environmen-tal contaminants acting at such low doses were found to be endocrine-disrupting chemicals, and most studies have thus focused on the sexual steroids system. However, the stress system, which produces glu-cocorticoids, has been overlooked.

*Corresponding authorEmail: [email protected] Centre for Studies on Human Stress,

Department 226, 7401 Hochelaga, Montreal, H1N3M5 Quebec, Canada

2 School of Psychoeducation, University of Montreal, Montreal, Quebec, Canada

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insults1. Moreover, because some contaminants have been recently banned or restricted, the elderly have been exposed to more contaminants than younger generations.

Toxic metalsThe best known threats to human health from toxic metals are associ-ated with lead and mercury. These toxic metals have been used in many different areas for thousands of years. Lead is one of the oldest known poisons. It has been used for at least 5000 years, in pipes for transport-ing water and in pigments for glazing ceramic. In ancient Rome, lead acetate was used to sweeten wine. Therefore, Romans might have ingested as much as a gram of lead per day, leading to the theory that lead poisoning might have contributed to the decline of the Roman Empire. Mercury was also used in the Roman Empire to sore teething pain in infants. More recently (from the14th to the 18th century), mercury was employed as a cure for syphilis, leading to the myth that Wolfgang Amadeus Mozart died from mercury poisoning in an attempt to cure syphilis. Although adverse health effects of toxic metals have been known for a long time, and their use has been restricted, exposure to toxic metals continues and is even increasing in some areas of the world (see Table 1 for common sources of exposure). For example, mercury is still used in gold mining in Africa and Latin America. In addition, even though lead has been banned as a gas-oline additive for on-road vehicles in developed countries, it remains a com-mon additive to gasoline for off-road use, including aircraft, racing cars, farm equipment and marine engines.

LeadMost lead in the environment comes from anthropogenic sources. Humans are, therefore, mainly exposed to lead from air, water and food. Inorganic lead accumulates in the skeleton and is slowly released from this body

compartment. Half-life of lead in the skeleton is about 25–30 years. In blood, lead is both free and bound to proteins and sulfhydryl compounds, in the latter case, preventing it to cross the blood–brain barrier. How-ever, the portion of blood-circulating lead that is free of ligand rapidly crosses the blood–brain barrier. The ability of lead to pass through this barrier is due to its ability to substi-tute for calcium ions. Indeed, lead is directly transported to the brain via the Ca-ATPase pumps. In foetus and infants, the developing blood–brain barrier is more permeable, allowing both free and bound lead to reach the brain. Elders are also more vul-nerable to lead exposure because of age-related bone demineralisation, releasing the accumulated lead into the blood.

MercuryMercury contamination occurs both from anthropogenic and natural sources. Most of the mercury found in the environment is in its inorganic form. However, mercury naturally found in soil, and deposited in soil or water from anthropogenic sources, is transformed into methylmercury through biomethylation. This organic form of mercury is highly toxic. Meth-ylmercury is accumulated in the liver and kidney of animals, and biomagni-fied through the food chain.

The main source of methylmer-cury for human beings is found in

food, particularly fish and marine mammal. Methylmercury is known to cross the placental and blood–brain barriers, accumulating in the foetus and the brain.

Persistent organic pollutants POPs are organic compounds that are highly resistant to chemical, photolytic or biological degrada-tion. These chemicals have very low water solubility and high lipid solubility. POPs are mostly halogen-ated, especially with chlorine mol-ecules. The single or often multiple halogen elements, such as fluorine, chlorine, bromine or iodine, bound to their structure are responsible for POPs stability to degradation and high lipid solubility (Figure 1). Therefore, POPs are persistent in the environment. They bioaccumulate in human and animal fat tissues, bio-magnifies in the food chain and can significantly alter the human health. POPs high lipid solubility enables them to pass through any biologi-cal barrier, such as the placental and blood–brain barriers. Virtually, all humans are thought to store POPs in fat tissues. POPs originate almost entirely from anthropogenic sources associated with the manufacture, use and disposal of organic chemicals (see Table 1 for common sources of exposure). POPs were massively pro-duced and used from the 1930s to 1980s. While some POPs have been banned or restricted, others remain.

Table 1 Common environmental contaminants and their sources of exposure

Environmental toxin Sources

Lead Smelters, battery plants, mine, lead-based paint, lead-based water pipes, gasoline and electronic waste

Mercury Chlor-alkali industry, thermometers, barometers, manometers, sphygmomanometers, fluorescent lamps, amalgam fillings and soil

PCBs Contaminated electrical equipment, stabilizer of PVC, food (mainly fish), soil water and air

Pesticides Pesticides manufacture, food, air, water, soil, sediments, plants and animals

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Human exposure to compounds that have been banned for more than 40 years continues mostly through the food chain, such as the pesticide dichlorodiphenyltrichloroethane. The traditional legacy POPs com-prises polychlorinated biphenyls (PCBs) and several chlorinated pesticides.

Environmental contaminants and mental healthIn adulthood, significant associations between ECs and mental health are well known even at very low levels of exposure, such as those shown between blood lead levels and depres-sive symptoms in the US population2.

In childhood, mental health disor-ders may be difficult to identify early, therefore, studies have focused mainly on neurobehavioural outcomes. Sig-nificant associations that have been revealed are mainly confined to emotional/behavioural adjustments (activity, attention, emotionality) and cognitive abilities (Table 2). More precisely, a comprehensive review of results from prospective PCB cohorts suggested that among the cognitive functions assessed in the different studies, detrimental effects have been more clearly established for executive functions11. From a more general per-spective, and according to Grandjean and Landrigan12, children’s exposure to ECs has even created a pandemic of neurodevelopmental disorders.

In the elderly population, studies have focused mainly on neurode-generative diseases and exposure to ECs in relation to cognitive

variability. Effects of exposure to ECs on impaired learning, memory and cognitive performances in the elderly have been documented (Table 3).

Until recently, the rule of thumb considered by regulatory agencies for public health recommendations was that high doses predict low doses effects. However, this approach is now disputed.

Dose of exposure and clinical management of contaminant exposureIn regulatory toxicology, there is a precept stating that higher doses will cause greater effects and conversely that substances considered toxic will be harmless in small doses. It is based on the early observations made by Paracelsus, the founder of toxicol-ogy, dating back to the 16th century. It is paraphrased as ‘The dose makes the poison’19. However, the validity of the Paracelsus logic has recently been challenged since several epi-demiological studies have shown that low dose exposure to ECs are associated with human diseases in disabilities20,21 and many chemicals even appear to have greater impact on human development at low doses than at higher doses. For example, the

Figure 1: Chemical structure of legacy persistent organic pollutants. PCB 153, polychlorinated biphenyl congener 153; DDT, dichlorodiphenyltrichloroethane.

Table 2 Some identified endocrine-disrupting chemicals with adverse mental health effects in children

Contaminant Mean level of exposure Effect Reference

Pb 3.5 (μg/dl) ↑ inattention 3

Pb 5.4 (μg/dl) ↑ impulsivity 4

Pb 5.4 (μg/dl) ↑ irritability 4

Pb 2.7 (μg/dl) ↑ hyperactivity 5

Pb 8.1 (μg/dl) ↓ cognitive ability 6

Hg 21.6 (μg/dl) ↑ inattention 5

Hg 21.6 (μg/dl) ↑ hyperactivity 5

Hg 22.9 (μg/dl) ↓ cognitive ability 7

PCBs 112.3 (ng/g lipids) ↑ inattention 8

PCBs 120.6 (μg/kg) ↑ impulsivity 4

PCBs 120.6 (μg/kg) ↑ irritability 4

Pesticides 13.7 (nmol/l) ↑ inattention 9

Pesticides 13.7 (nmol/l) ↑ hyperactivity 9

Pesticides 130 (nmol/l) ↓ cognitive ability 10

Pb, lead; Hg, mercury; PCBs, polychlorinated biphenyls.

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in the establishment of acceptable exposure levels. Indeed, they consist-ently decreased the acceptable level of exposure to chemicals as the study designed to evaluate neurodevelop-ment evolved.

Lead exposure and clinical managementLead has been the most studied EC, particularly in children. As a conse-quence, lead exposure in children is the contaminant with the most com-plete clinical screening and clinical management strategy. This example should be followed for other chemi-cals as soon as scientific knowledge becomes available. The World Health Organization (WHO) estimates that lead exposure accounts for 1% of the global burden of disease in children. In developing countries, 15%–20% of mental retardations are caused by exposure to lead. Not only is lead poisoning a tragedy for the child and his/her family, but it also carries a significant societal and economic cost. In the USA, burden of disease for lead poisoning in children is 20 times higher than for asthma and 120 times higher than for cancer; it is estimated at $43.4 billion annu-ally. On a population basis, for each 1 μg/dl increase in blood lead level, there is a reduction of 0.87 points in IQ. In addition, the rate of decline in intellectual impairment is greater at blood lead levels below 10 μg/dl than above22. In children, prena-tal exposure to 10 μg/dl blood lead level compared to 3 μg/dl results in a reduction of 4.8 points in IQ. This is a serious situation because in an entire population, a 5-point reduc-tion in IQ results in a 57% increase in ‘mentally retarded’ people requir-ing remedial assistance. The societal consequences are clearly enormous. Therefore, it is of critical importance to clinically manage lead exposure in children.

As previously evoked, acceptable blood lead levels in children was consistently revised according to

Table 3 Some identified endocrine-disrupting chemicals with adverse mental health effects in the elderly

ContaminantMean level of

exposureEffect Reference

Pb 5.3 (μg/dl) ↓ attention 13

Pb 27.7 (μg/dl) ↓ verbal memory 14

Pb 27.7 (μg/dl) ↓ learning 14

Pb 14 (μg/dl) ↓ executive functions 15

Hg 500–2000 (μg/l) ↓ attention and reaction time 16

Hg 500–2000 (μg/l) ↓ memory and learning 16

Hg 500–2000 (μg/l) ↓ visual memory 16

PCBs 78.2 (ppb) ↓ attention 17

PCBs 78.2 (ppb) ↓ visual memory 17

PCBs 78.2 (ppb) ↓ verbal memory 17

Pesticides 716 (ng/g lipids) ↓ memory 18

Pesticides 716 (ng/g lipids) ↓ memory 18

Pesticides 716 (ng/g lipids) ↓ learning 18

Pb, lead; Hg, mercury; PCBs, polychlorinated biphenyls.

lead-associated intelligence quotient (IQ) deficits observed in a recent pooled analysis were significantly greater at lower blood lead concen-trations22,23. Those chemicals follow a non-monotonic dose–response curve. Their slope reverses from neg-ative to positive or vice-versa, such as biological U-shaped or inversed U-shaped curves. The health implica-tions of non-monotonicity are strik-ing; it means that concentrations of chemicals in the environment are more of concern for human health than current testing conditions. In addition, the complications identi-fied by the epidemiological studies supporting the non-monotonicity of chemicals, such as cancer, obesity, heart disease, IQ and attention defi-cit hyperactivity disorder, contribute greatly to the steadily increasing bur-den of human disease and to the esca-lating health care cost throughout

the world. It is thus imperative to revise the 16th century dogma in ways that reflect modern scientific knowledge. Accordingly, the National Academy of Science’s Board on Envi-ronmental Studies and Toxicology conjointly with major public regu-latory agencies, including the Envi-ronmental Protection Agency, the National Institute of Environmental Health Science’s, the Food and Drug Administration and the National Institute of Child and Human Health Development, are preparing a report that will be released in the summer of 2013 about non-monotonic dose–response curves for chemicals. This report will help policy makers deter-mine appropriate testing strategies to capture adverse effects of chemi-cals following non-monotonic dose–response curves. Public regulatory agencies have already been faced with the problem of low dose effects

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the increasing knowledge in envi-ronmental health. The level of con-cern for lead in children gradually decreased from 60 μg/dl in 1960, 40 μg/dl in 1973, 30 μg/dl in 1975, 25 μg/dl in 1985, 10 μg/dl in 1991 to 5 μg/dl in 2012, as established by the CDC24. The current action level of 5 μg/dl in children may even be evaluated as too high, as suggested by the studies revealing adverse mental health outcome in children at 2.7 and 3.5 μg/dl3,5. In 2006, a study advocated that although no level of exposure to lead is safe, blood lead action level in children should be further reduced from 10 to 2 μg/dl, to prevent population from develop-mental neurotoxicity25. Nevertheless, the CDC established specific inter-vention recommendations that pae-diatric health care providers must follow based on the current blood lead action level of 5 μg/dl24.

Clinicians have an important role in preventing lead exposure and in managing lead-exposed children, as they are often the primary source of nutritional and lead-risk educa-tion received by parents24. Therefore, according to the current management recommendations, clinicians should: (1) provide anticipatory guidance about childhood lead poisoning and its prevention to minimise exposure before blood lead testing; (2) assess blood lead levels to identify exposed children, for whom primary preven-tion has failed; (3) intervene appro-priately when clinically indicated; (4) oversee monitoring of children with elevated blood lead levels, defined as a level above the refer-ence value of 5 μg/dl and (5) coor-dinate efforts with parents as well as local and state authorities to minimise risks to individual children and to assist communities in their primary prevention efforts24. The WHO reinforces the importance to screen blood lead level in children because lead poisoning is subclini-cal, it has nonspecific symptoms and its diagnostic relies exclusively on

laboratory screening26. Contrary to the past recommendations, when clinicians detect children blood lead level above the reference value (5 μg/dl), they must report it to the parents and public health officials to take action earlier to reduce the child’s future exposure to lead. To manage acute toxicity and reduce the body burden when blood lead levels are between 45 and 70 μg/dl, chela-tion is advised as a therapy. Chelation partly removes lead from the circu-lation using succimer as chelating agents. However, chelation is not rec-ommended in children with a blood lead level below 45 μg/dl because of the potential risk of adverse drug events and concerns about remobi-lised lead. For levels above 70 μg/dl, children must be immediately hospi-talised to perform chelation with suc-cimer simultaneously with EDTA26.

Although the current blood lead action level is still too high25, success-ful progress was made in the US to reduce lead exposure in children due to the management plan establish by public health regulatory agencies over the past four decades. In 1976, 88% of children aged 1–5 years had blood lead levels above 10 μg/dl. This percentage has markedly fallen to 4.4% in 1991 and to 1.6% in 1999. Then, blood lead levels in children substantially declined from 8.6% in 1999 to 2.6% in 2010. The CDC there-fore acquiesced that primary preven-tion is the only practical approach to preventing elevated blood lead levels in children27. The American Acad-emy of Paediatrics further advised that ‘childhood lead-poisoning policy should shift from case identification and management to primary preven-tion, to reach a goal of safe housing for all children’28.

The current blood lead action levels apply to children, but we could wonder whether it should also apply to elders. Indeed, no such screening recommendations are currently done in ageing people. We thus recommend clinicians to pay

attention to the emerging results in the field of environmental health, since researchers start understand-ing the process by which ECs impact health and it should change clini-cal management in near future. One plausible process by which lead and other ECs could impact neurodevel-opment at very low levels is through their action on hormonal systems20,21.

Endocrine-disrupting chemicalsEarly observations of reproductive organ malformations and abnormal sexual behaviours in wildlife first unveiled the ability of ECs to inter-fere with steroid hormone action and led to their definition as endocrine- disrupting chemicals. The WHO identifies an endocrine-disrupting chemical as ‘an exogenous substance or mixture that alters function(s) of the endocrine system and conse-quently causes adverse health effects in an intact organism, or its progeny, or (sub)populations’29. Furthermore, in a report published earlier in 2013, the WHO states that there is an urgent need for more research on the health outcome of endocrine disruptors. Although the sexual steroids system has been widely studied and will con-tinue to be, another steroids system has been poorly investigated in envi-ronmental health—the stress system.

The stress systemOver the past three decades, two major factors have been shown to sig-nificantly contribute to the increased inter-individual variability in behav-iour and cognitive performance across development. The first factor relates to genetics30 and the second relates to stress30,31. When individuals are faced with a stressful situation, activation of the hypothalamic– pituitary–adrenal (HPA) axis is induced (Figure 2). Glucocorticoids (GCs; cortisol in humans) are the final secretory products of HPA activation. Given the lipophilic properties of GCs, these adrenal steroid hormones can easily cross the blood–brain

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barrier and enter the brain, where they can influence brain functions and behaviour by way of binding to different receptor types. Two of the most important brain areas contain-ing GCs receptors are the hippocam-pus and frontal lobes, which are brain structures known to be involved in cognitive function such as memory32 and emotional/behavioural mal-adjustments, such as impulsivity33. Interestingly, deficits in HPA func-tioning has been related to impaired executive functions34, emotional/ behavioural adjustments35 in chil-dren and adolescents and cognitive impairments such as memory com-plaints in the elderly36.

Endocrine disruptors and the stress systemECs may disrupt the stress system, and thus have an impact on the release of

GCs following a stressful event. In wildlife, impairments in the stress sys-tem have been observed in relation to toxic metals exposure (lead, mercury) and environmental organic contami-nants (PCBs, solvents, pesticides) in fish37–39, amphibians40, birds41 and large mammals42. For example, Oskam et al.42 stated that the sum of pesticides combined with the sum of PCBs, and their interactions, explained over 25% of the variation in the cortisol con-centration. In laboratory studies with rodents, altered function of the system that control GCs has been reported following early exposure to PCBs43 and toxic metals44. Structure–activity relationship studies have shown that some PCBs acted as antagonists at the human GCs receptors45, and that dioxin-like PCBs altered GCs biosyn-thesis in human adrenocortical cells46. Moreover, a study has shown that a

low-level lead exposure increased GCs responses to acute stress in 9–10-year-old children47. A recent study reported a significant association between lead exposure and higher ACTH:CORT ratio in occupationally exposed par-ticipants, suggesting a lead-induced alteration of the HPA axis48.

The stress system could be the missing link between environmental contaminants and adverse mental healthTaken together, the current literature indicates that through their action on GCs, ECs could significantly impact behaviour and cognition in those who are the most at-risk—children and the elderly (Figure 3). Although research should continue in order to better characterise the mecha-nism of action of ECs on the stress system, unveiling this mechanism of action could also provide at-risk populations with ways to potentially decrease adverse effects of exposure to ECs. Indeed, psycho-social inter-ventions have started to emerge in the scientific literature, illustrat-ing that biological systems could be re-adapted, and thus leaving the way open for biological resilience49.

Critical appraisal of the validity of relevant articlesAccording to the Levels of Evidence of the Oxford Centre for Evidence-based Medicine, relevant articles cited in this review are from Level II and III. Their validity is therefore acceptable.

ConclusionChildren and ageing adults are more vulnerable to ECs exposure than adults. ECs have been shown to impair behavioural development and cognitive abilities even at low doses of exposure. As shown in this review, the endocrine-disrupting properties of ECs are a plausible mechanism through which these compounds could interfere with the stress sys-tem to induce neurobehavioural impairment.

Figure 2: Hypothalamic–pituitary–adrenal (HPA) axis. Experiencing an environmental stressor, as perceived by the brain, results in the activation of the HPA axis. The hypothalamus will thus secrete corticotrophin-releasing hormone (CRH). In the anterior lobe of the pituitary gland, CRH stimulates the secretion of adrenocorticotropic hormone (ACTH). The cortex of the adrenal glands will then produce glucocorticoids (cortisol in humans) in response to ACTH. Cortisol will then generate a stress response.

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Clinical applicabilityClinicians should be aware of the potential risks posed by endocrine-disrupting components. They should thus have access to straightforward and accurate health information tools to share with patients. Ultimately, in cases of lead or other chemical tox-icity, clinicians could recommend the testing of HPA axis functioning through diurnal cortisol assessment. Altered diurnal cortisol level could thus become a potential indicator of future neurobehavioural impair-ments, and thus might help clinicians to prevent children and/or ageing people to develop stress-related impairments in relations to ECs expo-sure. Finally, clinicians could recom-mend allostatic load assessment, an

indicator of physiological system impairment that is a clinical concept of chronic stress in patients at risk of ECs toxicity.

AcknowledgementWe gratefully thank Nathalie Wan for critical reading and revision of the manuscript.

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Figure 3: The stress system as the missing link between environmental con-taminants and adverse mental health. Endocrine disruptors, such as heavy met-als and persistent organic pollutants alter the hypothalamic–pituitary–adrenal axis, resulting in impairment of the stress system. Therefore, triggering adverse mental health which can be identified by several neurobehavioural outcomes. ACTH, adrenocorticotropic hormone; CRH, corticotrophin-releasing hormone; PCBs, polychlorinated biphenyls.

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Adverse effects of pollution on mental health: the … effects of pollution on mental health: ... the sexual steroids pathway. Conse- ... particularly fish and marine

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