US forces used Agent Orange (AO) during the Vietnam War and continued to store/test it at other locations after the war. AO is a powerful herbicide including dioxin, a highly toxic ingredient classified as a human carcinogen. The National Academies of Sciences, Engineering, and Medicine periodically review the literature on the health effects of AO exposure (AOE) and concluded in 2018 that there is sufficient evidence linking AO with a wide range of adverse health outcomes, including neurologic disorders (e.g., Parkinson’s disease). The VA has a list of medical disorders considered presumptive conditions related to AOE. More recently, AOE has been linked to a nearly double risk compared to those without AOE for receiving a dementia diagnosis. To our knowledge, no one has investigated the association of AOE to mild cognitive impairment (MCI), a condition thought to precede dementia.

We examined men in three waves of the Vietnam Era Twin Study of Aging (VETSA). In wave 3, participants self-reported yes/no to the question of whether they ever had prolonged or serious AOE. MCI was diagnosed by the Jak-Bondi approach. Impairment was defined as 2+ tests within a cognitive domain that were more than 1.5 standard deviations below normative means after adjusting for premorbid cognitive ability. In mixed effects models, we tested the effect of AOE on MCI status. Models were adjusted for age, ethnicity, and non-independence within twin pairs.

In wave 3, 12.6% (230) of 1167 participants reported AOE. Those with AOE data had mean ages of 51.1 (wave 1), 56.0 (wave 2), and 61.4 (wave 3). Those with data on both AOE and MCI numbered 861 (wave 1), 900 (wave 2), 1121 (wave 3), and 766 had AOE and MCI at all waves. AOE was significantly related to wave 2 MCI (p < .001), but not to waves 1 and 3 MCI. AOE was significantly associated with the number of time points at which someone met criteria for MCI (p = .011). Analyses were conducted on six cognitive domains used to diagnose MCI, using available participants per wave. At all 3 waves, AOE was significantly associated with lower scores in processing speed (p = .003, p = .004, p = .005, respectively), working memory (p < .001, p = .002, p = .008) and nearly significant at all waves for executive dysfunction (p < .001, p < .001, p = .050). There were two other significant associations [wave 2 memory (p = .038), wave 3 fluency (p = .024)]. The semantic fluency cognitive domain was unrelated to AOE in all waves.

AOE was consistently associated with lower processing speed, working memory, and executive dysfunction in males ages 51-61. It was also associated with the number of time points at which one met criteria for MCI in that age range, and with MCI in the mid-fifties. Findings support the idea of a risk for greater cognitive decline in those exposed to AO earlier in their lives, and with a risk for developing MCI.

The women who served in the 19901991 Persian Gulf War (GW) are unique in that they were the first group to have fewer restrictions in terms of military occupations and exposure to combat. Of the nearly 41,000 US troops who were women deployed to the GW, many were serving in frontline positions and were exposed to the same toxicants as their male counterparts. Toxicant exposures such as pesticide sprays and creams, oil well fires, diesel fuels, chemical and biological warfare (CBW) agents and anti-nerve gas (PB) pills have been found to result in cognitive impairments across a range of neuropsychological tests. Our research team has been following cohorts of women who were deployed to the GW and correlated exposures with neuropsychological outcomes. Overall, in small cohorts of women veterans we found that higher levels of exposures to pesticide sprays and creams and CBW are correlated with short-term memory, mood, and motor deficits. These findings were different from those of their male counterparts. In a recently developed data-repository we have compiled larger groups of women veterans to validate our prior findings.

The current study is an analysis of data from a national bio/data-repository (Boston Biorepository Recruitment and Integrative Network for Gulf War Illness; BBRAIN) which includes key data samples from prior GW studies that have been merged and combined into retrospective datasets. Data include general health and chronic symptom questionnaires, demographics, deployment and self-reported exposure histories (separated into no exposure, fewer than 7 days exposure and greater than or equal to 7 days exposure), as well as key neuropsychological test variables. Three separate datasets were combined to include 62 women. Exposures to chemical alarms, oil well fires, pesticide cream or spray, pesticide fogging, and PB pills were self-reported. Linear regression models were produced for each continuous cognitive outcome, modeled on a given exposure, and controlling for age, education level, PTSD, and other exposures.

Of the 62 women, the majority were White (77%). 74% of women surveyed were employed and 55% were married. 63% of women had at least a high school education. Deployed women who had > 7 days of exposure to pesticide sprays, CBW, smoke from oil well fires, and PB pills were more likely to show deficits in the areas of verbal learning and short-term memory (p < .03) and those with exposure to CBW, smoke from oil well fires, pesticides creams and PB pills had more errors on a test of executive functioning (p < .01). These data differ from the findings from cohorts of men.

These data validate the findings of our prior studies and add credence to the need for separate analyses for men and women. The unique outcomes may lead to individualized treatments for women veterans that may also help women with similar exposures from other deployments in addition to women with occupational exposures.

Fluoride exposure has been associated with thyroid dysfunction, but fluoride's impact on thyroid function in pregnancy is unclear, especially during early gestation when the fetus is dependent on maternal thyroid hormone. We examined the potential thyroid-disrupting effects of maternal fluoride exposure in pregnancy and tested whether thyroid disruption in pregnancy mediates the association between maternal fluoride exposure and child intelligence quotient (IQ) among Canadian mother-child dyads living in areas with optimal fluoridation.

We measured fluoride concentrations in drinking water and in spot urine samples collected in each trimester from pregnant women enrolled in the Maternal-Infant Research on Environmental Chemicals study. We also measured thyroid hormone (thyroid stimulating hormone [TSH], free thyroxine [FT4], and total thyroxine [TT4]) levels during the first trimester of pregnancy and categorized women as euthyroid (n=1301), subclinical hypothyroid (n=100), or primary hypothyroid (n=28). Those categorized as primary hypothyroid were combined with an additional 79 women who reported clinical diagnoses at time of study enrolment (total n=107). In a sample of 1508 women, we used logistic regression to estimate the association between fluoride exposure and risk of either subclinical or primary hypothyroidism, separately, and linear regression to estimate associations between fluoride exposure and women's thyroid hormone levels (TSH, FT4, TT4). We tested effect modification by child sex and thyroid peroxidase (TPO) antibody status. In a subsample of 439 mother-child pairs, we measured child Full-Scale IQ (FSIQ) at 3-4 years of age using the Wechsler Preschool and Primary Scale of Intelligence. We used linear regression to test associations between maternal hypothyroidism or thyroid hormone levels, and children's FSIQ scores. Finally, mediation analysis in the counterfactual framework was used to estimate the proportion of the effect of maternal fluoride exposure on child FSIQ mediated by maternal hypothyroidism, through evaluation of the natural direct (not through hypothyroidism) and indirect (through hypothyroidism) effects.

Using categorical measures of thyroid status, a 0.5 mg/L increase in water fluoride concentration was associated with a 1.64 (95% confidence interval [CI], 1.04 to 2.58) increased odds of primary hypothyroidism. This association was stronger among women with normal TPO antibody levels (< 5.61 IU/mL) (odds ratio, 2.80; 95% CI, 1.24 to 6.36). In contrast, we did not find a significant association between maternal urinary fluoride and hypothyroidism. For continuous measures of thyroid hormone levels, a 1 mg/L increase in maternal urinary fluoride was associated with a 35% (p=0.01) increase in TSH among women pregnant with a female fetus. In our subsample analyses, children born to women with primary hypothyroidism had lower FSIQ than children of euthyroid women, especially among boys (B, 8.78; 95% CI, -16.78 to -0.79). In contrast, maternal TSH, FT4, and TT4 levels were not significantly associated with child FSIQ scores. Maternal primary hypothyroidism did not significantly mediate the relationship between maternal water fluoride concentration and child FSIQ (p natural indirect effect= .35).

Fluoride in drinking water may increase the risk of hypothyroidism in pregnancy. Thyroid dysfunction in pregnancy may be one mechanism underlying developmental neurotoxicity of fluoride.

More than 30 years after the 199091 Gulf War (GW), approximately 200,000 veterans are still suffering from Gulf War Illness (GWI). Veterans who have this multi-symptom disorder experience impaired cognition, chronic pain, sustained fatigue, and gastrointestinal issues. GWI is believed to be associated with neurotoxicant exposures during the war. Prior research has shown cognitive deficits in combined samples of male and female GW veterans with GWI. These studies have shown that veterans with GWI have cognitive decrements in memory, learning and sustained attention. Studies have yet to compare neuropsychological outcomes by sex. This is mainly due to the lack of collected data on women GW veterans in the past. This study aims to analyze neuropsychological differences in males compared with female veterans with GWI and in those with neurotoxicant exposures from the Boston, Biorepository and Integrative Network (BBRAIN) for GWI repository dataset.

The total sample included 297 veterans with GWI (women n=50, men n=247) who were deployed to the 1990-91 Gulf War with an average age of 52 years. GWI case status was defined by the Kansas GWI criteria. Neuropsychological data including the Conners Continuous Performance Test Third Edition (CPT3), Delis-Kaplan Executive Function System (D-KEFS) Color-Word Interference Test, and the California Verbal Learning Test (CVLT-II) were combined from the BBRAIN repository datasets. War-related exposures, including chemical weapons, anti-nerve gas pills and pesticides were measured by a self-reported survey. Multiple linear regression was used to analyze the association between sex, war-related exposures, and neuropsychological test score outcomes.

After adjusting for age, education level and PTSD, men had a significantly lower number of words correct in the CVLT-II learning Trials 1-5, short delay recall and long delay recall compared with women veterans (p<0.05). The two groups also differed significantly in CPT3 commission scores, and total time on the D-KEFs Color-Word Inference total times in Trials 1 and 2 with men performing worse (p<0.05). Reported exposure to chemical weapons, pesticides, pyridostigmine bromide (PB) anti-nerve gas pills or smoke from oil well fires were all significantly associated with fewer words correctly recalled on all learning trials of the CVLT-II, long delay, and short delay to a greater degree in men as compared to women (p<0.05). Reported exposure to chemical weapons or smoke from oil well fires were significantly associated with more commission errors on CPT3 in men with GWI (p<0.05). Chemical alarms, smoke from oil well fires and PB were associated with slower response time on the Color-Word Interference test Trial 1 in men compared with women veterans.

In this study, men with GWI demonstrated significantly poorer performance in verbal memory, learning, response speed and attention. Male veterans reporting neurotoxicant exposures during the war also showed worse learning and verbal memory, impulsivity and response speed decrements compared to exposed women veterans. Future research should consider men and women separately when examining outcomes from war-related exposures.

Early life exposures to lead, mercury, polychlorinated biphenyls (PCBs), polybromide diphenyl ethers (PBDEs), organophosphate pesticides (OPPs), and phthalates have been associated with diminished IQ scores in children. Some studies suggest that these neurotoxicants impact boys and girls differently. We conducted a systematic review and meta-analysis to identify and quantify sex differences in IQ deficits from pre- and post-natal exposures to these developmental neurotoxicants.

We used PubMed and PsychINFO to screen abstracts of articles published between January 1, 1950 and December 31, 2021 for empirical studies of six neurotoxicants [lead, mercury, PCBs, PBDEs, OPPs, and/or phthalates] that (1) used an individualized biomarker; (2) measured exposure during the prenatal period or within the first six years of life; and (3) provided different effect estimates on children's intellectual abilities by sex. We assessed each study for risk of bias using Navigation Guide (Woodruff & Sutton, 2014). For studies with combinable data, we performed separate random effects meta-analyses for boys and girls with subgroup analyses by neurotoxicant. To homogenize the magnitude of effect observed in each study, we recalculated results to be expressed as the absolute change in intellectual abilities for a relative change of 1.5 times (i.e., 50% increase) in the exposure variable.

Of 3205 studies screened, 53 met inclusion criteria: 34 evaluated prenatal exposure, 11 postnatal exposure, and 8 both pre- and post-natal exposure. We generally rated these studies as "low" to "probably low" risk of bias. Among the studies examining prenatal exposure, 27 reported no significant differences between the sexes, 7 found negative associations in boys, 4 found negative associations in girls, 5 found negative nonsignificant associations in boys and positive nonsignificant associations in girls, and 3 found no clear pattern, where differences by sex depended on the specific phthalate compound or outcome measurement. Among the studies examining postnatal exposure, 14 reported no significant differences between the sexes, 1 found a negative association in boys, 2 found negative associations in girls, and 2 found positive associations for either boys or girls. In our meta-analysis of 16 studies (4 lead, 4 mercury, 2 PBDEs, 2 OPPs, 4 phthalates), we found that prenatal exposure to developmental neurotoxicants was associated with decreased full-scale intelligence in boys (B = -0.26; 95% CI: -0.45, -0.08), but not girls (B = 0.09; 95% CI: -0.14, 0.31). In subgroup analyses by neurotoxicant, prenatal exposure to lead (B = -1.07; 95% CI: -1.63, -0.52), and ZPBDEs (B = -0.57; 95% CI: -1.14, -0.01) were associated with decreased full-scale intelligence in boys, whereas the girls' effect sizes were consistently near zero.

During fetal development, boys appear to be more vulnerable than girls to IQ deficits from neurotoxic exposures, and especially from lead and PBDEs. More research is needed to examine the nuanced sex-specific effects found for postnatal exposures to toxic chemicals.

Exposure to toxic chemicals during early brain development increases the risk of neurodevelopmental problems in children. Parents' and prospective parents' understanding of the impact of toxic chemicals on brain development and the efficacy of translation tools for children's environmental health literacy are poorly understood. We developed and validated a questionnaire, PRevention of Toxic chemicals in the Environment for Children Tool (PRoTECT) to assess knowledge of toxic chemicals and neurodevelopment, intentions to reduce exposures to toxic chemicals, and preferences for actions by government and industry to prevent neurodevelopmental disorders. Using PRoTECT, we surveyed people of child-bearing age across five countries (Canada, United States (US), United Kingdom (UK), India, and Australia) to identify general patterns of responses on this questionnaire by demographic characteristics, including country, age, gender, parental status, pregnancy status, and education. We also employed a randomized control design to examine the efficacy of a knowledge translation video to instill knowledge and prompt behavioral changes to reduce exposures to toxic chemicals immediately following its presentation and after a six-week follow-up period.

We recruited 15,594 participants, ages 18 to 45, via CloudResearch's Prime Panels between October-December 2021. After completing the PRoTECT survey, participants were randomly assigned to watch the video Little Things Matter: Impact of Toxic Chemicals on Brain Development (i.e., the experimental group) or to serve as the control group. Next, both groups answered a series of questions to assess their knowledge of toxic chemicals, their intentions to reduce exposures to toxic chemicals, and barriers to changing their behaviours. After six-weeks, we recontacted a subset (N=4,842) of participants to repeat PRoTECT and answer the same series of behavioural questions assessing whether they modified any of their behaviours to reduce exposure and why or why not.

Most participants (i.e., 75-85%) agreed that toxic chemicals can impact brain development and endorsed preferences (∼85%) for allocating more resources to prevent neurodevelopmental disorders, especially people with higher education, parents and pregnant women, and people who lived in India. Despite this, a large proportion of participants (∼50%) trusted industry and believed that government effectively regulated toxic chemicals. After the six-week follow-up, experimental participants showed greater changes in scores on PRoTECT (i.e., between 5-15% change), indicating greater knowledge about harms posed by toxic chemicals, more intentions to reduce exposure, and stronger preferences for prevention as compared to the control group. Differences were larger among people from the US, those who were more highly educated, and people in their thirties. However, the differences between groups in making behavioural changes to reduce exposures were attenuated at the six-week follow up as compared to baseline. Significant barriers to reduce exposure to toxic chemicals were reported by both groups and included cost, inconvenience, and not knowing how to determine whether a product is non-toxic or where to purchase non-toxic products.

We observed greater knowledge and concerns about toxic chemicals among more affluent respondents, pregnant women and parents, and people living in India across both groups. While the video enhanced participants' knowledge about toxic chemicals and intentions to reduce exposure, they indicated that barriers hindered them from making behavioral changes.

Gulf War Illness (GWI) is a debilitating multi-symptom condition that affects nearly a third of 1990-91 Gulf War (GW) veterans. Symptoms include chronic pain, debilitating fatigue, gastrointestinal issues, and cognitive decrements. Prior studies have documented reduced cognitive functioning in this affected population, particularly in the areas of memory, attention and response inhibition. To date, research has focused on cognitive functioning in male and female veterans together. Very limited research has reported on GW women's cognitive functioning separately mostly due to scarcity of data on women veterans. In this study, we had the unique opportunity to utilize a newly combined neuropsychological test dataset from women GW veterans in the Boston, Biorepository and Integrative Network (BBRAIN) for GWI. The aim was to compare neuropsychological outcomes with toxicant exposures in women veterans with and without GWI.

Cognitive data from the BBRAIN biorepository was used for this study. The sample consisted of 62 women veterans who were deployed to the Persian Gulf War from 1990-91. Neuropsychological test scores included the Conners Continuous Performance Test Third Edition (CPT3), Delis-Kaplan Executive Function System (D-KEFS) Color-Word Interference, and the California Verbal Learning Test Second Edition (CVLT-II). War-related exposure to chemical weapons, anti-nerve gas pills and pesticides were measured by a self-reported survey. For analysis, war-related exposure was classified into three groups: controls with 0-6 days of exposure; cases with 0-6 days of exposure and cases with 7 or more days of exposure. Multiple linear regression modeling was used to measure differences in neuropsychological scores across the three groups by each war-related exposure.

After adjusting for age, education and other exposures, an increase in duration of exposure to pesticides was significantly associated with worse CPT3 commission errors, fewer words correct in the CVLT-II trials 1-5, and an increase in self-corrected errors on DKEFS Color-Word Interference Test Trials 1, 2 and 4 (p<0.05). More days reported hearing chemical alarms and seeing smoke from oil well fires was significantly associated with fewer words correct on all CVLT-II trials, and more self-corrected errors on Color-Word Interference Trials 2 and 4 (p<0.05). An increase in exposure duration to pyridostigmine bromide anti-nerve gas pills was associated with fewer words correct on the CVLT-II learning Trials 1-5 and short delay recall and an increase in self-corrected errors on Color-Word Interference Trials 2, 3, and 4 (p<0.05). When associations were adjusted for PTSD, all significant associations stayed constant (p<0.05).

In this study, women veterans with GWI who had higher levels of exposure to pesticides, oil well fires and who took more antinerve gas pills during the war are showing increased learning difficulties and more deficits in attention and response inhibition. Future research should examine if similar patterns of neuropsychological symptoms are also present in male GW veterans with higher war-time related toxicant exposures.

In recent decades, a large body of evidence has linked prenatal exposure to environmental neurotoxins to adverse intellectual, neurodevelopmental, and psychiatric outcomes in offspring. This evidence has clearly highlighted the widespread impact of neurotoxin exposure on the developing brain; however, it is unclear how and why these exposures alter brain development in a way that appears to increase risk for multiple, seemingly disparate outcomes.

Shifting our focus from describing links between neurotoxin exposure and symptoms of offspring mental/cognitive problems considered categorically, to investigating how neurotoxins adversely affect domains of functioning known to cut across risk for multiple problems in offspring may be critical to answering these questions. This presentation will discuss how combining research in developmental neurotoxicology with novel systems that take dimensional approaches to understanding emotions, cognition, and behaviour (i.e., the NIHM Research Domain Criteria (RDoC)) may provide a fruitful future research direction for the field. The RDoC framework aims to understand neuropsychological outcomes (i.e., mental health, mental illness, IQ) across major domains of human emotion, cognition, behaviour, and social functioning, rather than within distinct diagnostic categories.

Using lead exposure as an example, this presentation will outline a framework for how researchers can use this dimensional approach to develop more specific hypotheses that can reveal how and why neurotoxin exposure increases risk for multiple adverse outcomes and elucidate the mechanisms that may underly these links.

Additionally, given that adverse development within domains of functioning can be detected prior to the onset of full-blown diagnoses, this research could enable us to develop more precise, targeted prevention and risk reduction campaigns. Adopting a dimensional framework will provide a more complete picture of the overall impact of prenatal exposure to neurotoxins - critical for informing public health policy.

Older patients may be more vulnerable to the deleterious effect of depressive episodes on delayed narrative memory, a cognitive task which reflects hippocampal activity. We aimed to disentangle which factors could explain such increased vulnerability in the elderly, including the poorer response to treatment, a longer lifetime exposure to past depressive episodes, and lower baseline memory skills.

From an initial sample of 8,229 depressed outpatients, we focused on the 2,424 treatment responders, and compared older (65 years old and over, N = 233) to younger (N = 2,191) ones. These patients were included through general practitioners’ assessment and tested for the Wechsler delayed paragraph recall index, a valid and sensitive test assessing verbal declarative memory (and a marker of the hippocampal function), at baseline and after six weeks of treatment.

As expected, older patients after response to antidepressants showed decreased narrative memory abilities compared to younger ones. As baseline memory performance and residual depressive symptoms were also found in excess in this sample, they could act as confounders. Indeed, after controlling for these two factors, the role of age in memory performance after treatment response was ruled out.

The potential “toxicity” of a depressive episode to cognitive functions related to the hippocampus may not be more critical in older patients compared to younger ones. Limiting remaining depressive symptoms in older depressed patients might be a way to counteract the observed worsening of memory functions in depressed patients.