PON1 and neurodevelopment in children from the CHAMACOS study exposed to organophosphate pesticides in utero

Background

Paraoxonase 1 (PON1) detoxifies oxon derivatives of some organophosphate (OP) pesticides, and its genetic polymorphisms influence enzyme activity and quantity. We previously reported that maternal urinary concentrations of dialkyl phosphate (DAP) metabolites, a marker of OP pesticide exposure, were related to poorer mental development and maternally reported symptoms consistent with pervasive developmental disorder (PDD) in 2-year-olds participating in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study.

Objective

We determined whether PON1 genotypes and enzyme measurements were associated with child neurobehavioral development and whether PON1 modified the association of in utero exposure to OPs (as assessed by maternal DAPs) and neurobehavior.

Methods

We measured DAP concentrations in maternal urine during pregnancy, PON1₁₉₂ and PON1₋₁₀₈ genotypes in mothers and children, and arylesterase (ARYase) and paraoxonase (POase) in maternal, cord, and 2-year-olds’ blood. We assessed 353 2-year-olds on the Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development and queried their mothers on the Child Behavior Checklist to obtain a score for PDD.

Results

Children with the PON1_−108T allele had poorer MDI scores and somewhat poorer PDI scores. Children were less likely to display PDD when they or their mothers had higher ARYase activity and when their mothers had higher POase activity. The association between DAPs and MDI scores was strongest in children with PON1_−108T allele, but this and other interactions between DAPs and PON1 polymorphisms or enzymes were not significant.

Conclusion

PON1 was associated with child neurobehavioral development, but additional research is needed to confirm whether it modifies the relation with in utero OP exposure.     

Serum Cholinesterase Inhibition in Relation to Paraoxonase-1 (PON1) Status among Organophosphate-Exposed Agricultural Pesticide Handlers

Background

Animal studies have demonstrated that low paraoxonase-1 (PON1) status (i.e., low catalytic efficiency and/or low plasma PON1 activity) is associated with neurotoxic effects after exposure to several organophosphate (OP) insecticides. However, few human studies have investigated associations between PON1 status and intermediate end points, such as serum cholinesterase [butyrylcholinesterase (BuChE)] inhibition, among OP-exposed individuals.

Objectives

We evaluated the relation between plasma PON1 status and BuChE inhibition among OP-exposed agricultural pesticide handlers.

Methods

Agricultural pesticide handlers in Washington State were recruited during the 2006 and 2007 spray seasons when they were seen for follow-up ChE testing by collaborating medical providers as part of a statewide monitoring program. Blood samples were collected from 163 participants and tested for PON1 status based on plasma PON1 activity [arylesterase (AREase)] and PON1 Q192R genotype. We evaluated percent change in BuChE activity from baseline level in relation to PON1 status.

Results

We observed significantly greater BuChE inhibition among QQ homozygotes relative to RR homozygotes (p = 0.036). Lower levels of plasma PON1 activity were significantly associated with greater BuChE inhibition (p = 0.004). These associations remained after adjustment for year, days since baseline test, age, and OP exposure in the last 30 days.

Conclusions

We found that both low PON1 catalytic efficiency (i.e., the Q192 alloform) and low plasma PON1 activity were associated with BuChE inhibition among OP-exposed agricultural pesticide handlers. Corroborative findings from future studies with prospective collection of blood samples for PON1 testing, more sensitive markers of OP-related effects, and larger sample sizes are needed.     

Racial Differences in Paraoxonase-1 (PON1): A Factor in the Health of Southerners?

Background

The southern United States (excluding Florida) has the highest age-adjusted rate of cardiovascular disease (CVD) in the country, with African Americans having a higher prevalence of CVD than Caucasians. Paraoxonase-1 (PON1), an enzyme associated with high-density lipoprotein particles, participates both in the hydrolysis of oxidized lipids (thus protecting against atherosclerosis) and in the hydrolysis of organophosphates. Higher paraoxonase activity has been associated with lower risk of atherosclerosis.

Objectives

In this study we characterized the distribution of the functional PON1_Q192R polymorphisms (PON status as assessed by diazoxonase to paraoxonase ratios) and the PON1 activity levels in 200 adult males and females of both races (50 in each race/sex class) from the southern United States from commercially obtained blood bank serum samples.

Methods

We used spectrophotometric methods with serum to determine PON1 status, arylesterase activities (phenyl acetate hydrolysis), and levels of cotinine and C-reactive protein (CRP).

Results

African Americans had higher paraoxonase activities but lower diazoxonase activities than did Caucasians, consistent with African Americans having a lower proportion of the functional genotype QQ (QQ 15%, QR 34%, RR 44%, 7% indeterminate), than did Caucasians (QQ 60%, QR 31%, RR 7%, 2% indeterminate). Cotinine levels indicated that all samples came from non-smokers and that CRP levels were higher in African Americans than in Caucasians and higher in females than in males. CRP levels showed no association with paraoxonase activities.

Conclusions

These data present initial observations for use in characterizing the poorer cardiovascular health status of the population in the southern United States and more specifically southern African Americans.     

Childhood Brain Tumors,Residential Insecticide Exposure,and Pesticide Metabolism Genes

Background

Insecticides that target the nervous system may play a role in the development of childhood brain tumors (CBTs). Constitutive genetic variation affects metabolism of these chemicals.

Methods

We analyzed population-based case–control data to examine whether CBT is associated with the functional genetic polymorphisms PON1_C–108T, PON1_Q192R, PON1_L55M, BCHE_A539T, FMO1_C–9536A, FMO3_E158K, ALDH3A1_S134A, and GSTT1 (null). DNA was obtained from newborn screening archives for 201 cases and 285 controls, ≤ 10 years of age, and born in California or Washington State between 1978 and 1990. Conception-to-diagnosis home insecticide treatment history was ascertained by interview.

Results

We observed no biologically plausible main effects for any of the metabolic polymorphisms with CBT risk. However, we observed strong interactions between genotype and insecticide exposure during childhood. Among exposed children, CBT risk increased per PON1_–108T allele [odds ratio (OR) = 1.8; 95% confidence interval (CI), 1.1–3.0] and FMO1_–9536A (*6) allele (OR = 2.7; 95% CI, 1.2–5.9), whereas among children never exposed, CBT risk was not increased (PON1: OR = 0.7; 95% CI, 0.5–1.0, interaction p = 0.005; FMO1: OR = 1.0; 95% CI, 0.6–1.6, interaction p = 0.009). We observed a similar but statistically nonsignificant interaction between childhood exposure and BCHE_A539T (interaction p = 0.08). These interactions were present among both Hispanic and non-Hispanic white children.

Conclusion

Based on known effects of these variants, these results suggest that exposure in childhood to organophosphorus and perhaps to carbamate insecticides in combination with a reduced ability to detoxify them may be associated with CBT. Confirmation in other studies is required.     

Effect of cigarette smoking on paraoxonase?1 activity according to PON1 L55M and PON1 Q192R gene polymorphisms

Objective

This study aims to investigate the effect of cigarette smoking on paraoxonase 1 (PON1) activity according to PON1 L55M and PON1 Q192R gene polymorphisms.

Materials and methods

Our sample included 300 voluntary subjects: 138 nonsmokers and 162 current smokers aged 38.47 ± 21.91 and 35.55 ± 16.03 years, respectively. PON1 activity was determined by kinetic methods. L55M and Q192R gene polymorphisms of PON1 were determined by multiplex polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP).

Results

We found in smokers a significant decrease of PON1 activity before and after adjustment. We noted a significant association between smoking status and lower PON1 activity [odds ratio (OR) = 3.03, confidence interval 95% = 1.5–5.9, p = 0.001]. In smokers, there was significant association between PON1 activity and PON1 L55M polymorphisms (p = 0.01). Also, the 55MM genotype presented the lowest paraoxonase activity, while the 55LL genotype showed the highest one. After adjustment for confounding variables, smokers with PON1 L55M polymorphism had the highest risk for lower PON1 activity; however, PON1 Q192R genotype might protect smokers from decrease in PON1 activity. We found significant interaction between the effect of cigarette smoking and both PON1 L55M and PON1 Q192R polymorphisms on lower PON1 activity.

Conclusions

Cigarette smoking was significantly associated with decrease in PON1 activity. Moreover, PON1 L55M polymorphism predisposes smokers to decreased PON1 activity in contrast to PON1 Q192R genotype.     

Polymorphisms in GSTT1, GSTZ1, and CYP2E1, Disinfection By-products,and Risk of Bladder Cancer in Spain

Background

Bladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water.

Objectives

In this study we investigated the combined influence of DBP exposure and polymorphisms in glutathione S-transferase (GSTT1, GSTZ1) and cytochrome P450 (CYP2E1) genes in the metabolic pathways of selected by-products on bladder cancer in a hospital-based case–control study in Spain.

Methods

Average exposures to trihalomethanes (THMs; a surrogate for DBPs) from 15 years of age were estimated for each subject based on residential history and information on municipal water sources among 680 cases and 714 controls. We estimated effects of THMs and GSTT1, GSTZ1, and CYP2E1 polymorphisms on bladder cancer using adjusted logistic regression models with and without interaction terms.

Results

THM exposure was positively associated with bladder cancer: adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.2 (0.8–1.8), 1.8 (1.1–2.9), and 1.8 (0.9–3.5) for THM quartiles 2, 3, and 4, respectively, relative to quartile 1. Associations between THMs and bladder cancer were stronger among subjects who were GSTT1 +/+ or +/− versus GSTT1 null (p_interaction = 0.021), GSTZ1 rs1046428 CT/TT versus CC (p_interaction = 0.018), or CYP2E1 rs2031920 CC versus CT/TT (p_interaction = 0.035). Among the 195 cases and 192 controls with high-risk forms of GSTT1 and GSTZ1, the ORs for quartiles 2, 3, and 4 of THMs were 1.5 (0.7–3.5), 3.4 (1.4–8.2), and 5.9 (1.8–19.0), respectively.

Conclusions

Polymorphisms in key metabolizing enzymes modified DBP-associated bladder cancer risk. The consistency of these findings with experimental observations of GSTT1, GSTZ1, and CYP2E1 activity strengthens the hypothesis that DBPs cause bladder cancer and suggests possible mechanisms as well as the classes of compounds likely to be implicated.     

Neonatal Organophosphorus Pesticide Exposure Alters the Developmental Trajectory of Cell-Signaling Cascades Controlling Metabolism: Differential Effects of Diazinon and Parathion

Background

Organophosphorus pesticides (OPs) are developmental neurotoxicants but also produce lasting effects on metabolism.

Objectives/methods

We administered diazinon (DZN) or parathion (PRT) to rats on postnatal days 1–4 at doses straddling the threshold for systemic signs of exposure and assessed the effects on hepatic and cardiac cell signaling mediated through the adenylyl cyclase (AC) cascade.

Results

In the liver, DZN elicited global sensitization, characterized by parallel up-regulation of AC activity itself and of the responses to stimulants acting at β-adrenergic receptors, glucagon receptors, or G-proteins. The effects intensified over the course from adolescence to adulthood. In contrast, PRT elicited up-regulation in adolescence that waned by adulthood. Superimposed on these general patterns were effects on glucagon receptor coupling to AC and on responses mediated through the G_i inhibitory protein. The effects on the liver were more substantial than those in the heart, which displayed only transient effects of DZN on AC function in adolescence and no significant effects of PRT. Furthermore, the hepatic effects were greater in magnitude than those in a brain region (cerebellum) that shares similar AC cascade elements.

Conclusions

These findings indicate that OPs alter the trajectory of hepatic cell signaling in a manner consistent with the observed emergence of prediabetes-like metabolic dysfunction. Notably, the various OPs differ in their net impact on peripheral AC signaling, making it unlikely that the effects on signaling reflect their shared property as cholinesterase inhibitors.     

Perinatal Exposure to Traffic-Related Air Pollution and Atopy at 1 Year of Age in a Multi-Center Canadian Birth Cohort Study

Background

The role of traffic-related air pollution (TRAP) exposure in the development of allergic sensitization in children is unclear, and few birth cohort studies have incorporated spatiotemporal exposure assessment.

Objectives

We aimed to examine the association between TRAP and atopy in 1-year-old children from an ongoing national birth cohort study in four Canadian cities.

Methods

We identified 2,477 children of approximately 1 year of age with assessment of atopy for inhalant (Alternaria, Der p, Der f, cat, dog, cockroach) and food-related (milk, eggs, peanuts, soy) allergens. Exposure to nitrogen dioxide (NO₂) was estimated from city-specific land use regression models accounting for residential mobility and temporal variability in ambient concentrations. We used mixed models to examine associations between atopy and exposure during pregnancy and the first year of life, including adjustment for covariates (maternal atopy, socioeconomic status, pets, mold, nutrition). We also conducted analyses stratified by time-location patterns, daycare attendance, and modeled home ventilation.

Results

Following spatiotemporal adjustment, TRAP exposure after birth increased the risk for development of atopy to any allergens [adjusted odds ratio (aOR) per 10 μg/m³ NO₂ = 1.16; 95% CI: 1.00, 1.41], but not during pregnancy (aOR = 1.02; 95% CI: 0.86, 1.22). This association was stronger among children not attending daycare (aOR = 1.61; 95% CI: 1.28, 2.01) compared with daycare attendees (aOR = 1.05; 95% CI: 0.81, 1.28). Trends to increased risk were also found for food (aOR = 1.17; 95% CI: 0.95, 1.47) and inhalant allergens (aOR = 1.28; 95% CI: 0.93, 1.76).

Conclusion

Using refined exposure estimates that incorporated temporal variability and residential mobility, we found that traffic-related air pollution during the first year of life was associated with atopy.

Citation

Sbihi H, Allen RW, Becker A, Brook JR, Mandhane P, Scott JA, Sears MR, Subbarao P, Takaro TK, Turvey SE, Brauer M. 2015. Perinatal exposure to traffic-related air pollution and atopy at 1 year of age in a multi-center Canadian birth cohort study. Environ Health Perspect 123:902–908; http://dx.doi.org/10.1289/ehp.1408700     

The influence of living near roadways on spirometry and exhaled nitric oxide in elementary schoolchildren

Background

Living near major roadways has been associated with an increase in respiratory symptoms, but little is known about how this relates to airway inflammation.

Objective

We assessed the effects of living near local residential roadways based on objective indicators of ventilatory function and airway inflammation.

Methods

We estimated ambient air pollution, resolved to the level of the child’s neighborhood, using a land-use regression model for children 9–11 years of age. We also summed the length of roadways found within a 200-m radius of each child’s neighborhood. We had measurements of both air pollution exposure and spirometry for 2,328 children, and also had measurements of exhaled nitric oxide (eNO) for 1,613 of these children.

Results

Each kilometer of local roadway within a 200-m radius of the home was associated with a 6.8% increase in eNO (p = 0.045). Each kilometer of any type of roadway (local, major, highway) was also associated with an increase in eNO of 10.1% (p = 0.002). Each microgram per cubic meter increase in PM_2.5 was associated with a 3.9% increase in eNO (p = 0.058) and 0.70% decrease in forced vital capacity (FVC) expressed as a percentage of predicted (p = 0.39). Associations between roadway density and both forced expired volume in 1 sec and FVC were negative but not statistically significant at p < 0.05.

Conclusion

Traffic from local neighborhood roadways may cause airway inflammation as indicated by eNO. This may be a more sensitive indicator of adverse air pollution effects than traditional measures of ventilatory function.     

Serum Polybrominated Diphenyl Ether (PBDE) Levels Are Higher in Children (2–5 Years of Age) than in Infants and Adults

Background

Polybrominated diphenyl ethers (PBDEs) are used as flame retardants in many products and have been detected in human samples worldwide. Limited data show that concentrations are elevated in young children.

Objectives

We investigated the association between PBDEs and age with an emphasis on young children from Australia in 2006–2007.

Methods

We collected human blood serum samples (n = 2,420), which we stratified by age and sex and pooled for analysis of PBDEs.

Results

The sum of BDE-47, -99, -100, and -153 concentrations (∑₄PBDE) increased from 0–0.5 years (mean ± SD, 14 ± 3.4 ng/g lipid) to peak at 2.6–3 years (51 ± 36 ng/g lipid; p < 0.001) and then decreased until 31–45 years (9.9 ± 1.6 ng/g lipid). We observed no further significant decrease among ages 31–45, 45–60 (p = 0.964), or > 60 years (p = 0.894). The mean ∑₄PBDE concentration in cord blood (24 ± 14 ng/g lipid) did not differ significantly from that in adult serum at ages 15–30 (p = 0.198) or 31–45 years (p = 0.140). We found no temporal trend when we compared the present results with Australian PBDE data from 2002–2005. PBDE concentrations were higher in males than in females; however, this difference reached statistical significance only for BDE-153 (p = 0.05).

Conclusions

The observed peak concentration at 2.6–3 years of age is later than the period when breast-feeding is typically ceased. This suggests that in addition to the exposure via human milk, young children have higher exposure to these chemicals and/or a lower capacity to eliminate them.     

Urinary Porphyrin Excretion in Neurotypical and Autistic Children

Background

Increased urinary concentrations of pentacarboxyl-, precopro- and copro-porphyrins have been associated with prolonged mercury (Hg) exposure in adults, and comparable increases have been attributed to Hg exposure in children with autism (AU).

Objectives

This study was designed to measure and compare urinary porphyrin concentrations in neurotypical (NT) children and same-age children with autism, and to examine the association between porphyrin levels and past or current Hg exposure in children with autism.

Methods

This exploratory study enrolled 278 children 2–12 years of age. We evaluated three groups: AU, pervasive developmental disorder-not otherwise specified (PDD-NOS), and NT. Mothers/caregivers provided information at enrollment regarding medical, dental, and dietary exposures. Urine samples from all children were acquired for analyses of porphyrin, creatinine, and Hg. Differences between groups for mean porphyrin and Hg levels were evaluated. Logistic regression analysis was conducted to determine whether porphyrin levels were associated with increased risk of autism.

Results

Mean urinary porphyrin concentrations are naturally high in young children and decline by as much as 2.5-fold between 2 and 12 years of age. Elevated copro- (p < 0.009), hexacarboxyl- (p < 0.01) and pentacarboxyl- (p < 0.001) porphyrin concentrations were significantly associated with AU but not with PDD-NOS. No differences were found between NT and AU in urinary Hg levels or in past Hg exposure as determined by fish consumption, number of dental amalgam fillings, or vaccines received.

Conclusions

These findings identify disordered porphyrin metabolism as a salient characteristic of autism. Hg exposures were comparable between diagnostic groups, and a porphyrin pattern consistent with that seen in Hg-exposed adults was not apparent.     

Goitrogenic Anions,Thyroid-Stimulating Hormone,and Thyroid Hormone in Infants

Background

Environmental exposure of infants to perchlorate, thiocyanate, nitrate, might interfere with thyroid function. U.S. women with higher background perchlorate exposure have higher thyroid-stimulating hormone (TSH) and lower thyroxine (T₄). There are no studies with individual measures of thyroid function and these goitrogens available in infants.

Objective

We examined the association of urinary perchlorate, nitrate, iodide, and thiocyanate with urinary T₄ and TSH in infants and whether that association differed by sex or iodide status.

Methods

We used data and samples from the Study of Estrogen Activity and Development, which assessed hormone levels of full-term infants over the first 12 months of life. The study included 92 full-term infants between birth and 1 year of age seen up to four times. Perchlorate, thiocyanate, nitrate, and iodide were measured in 206 urine samples; TSH and T₄ and were measured in urines and in 50 blood samples.

Results

In separate mixed models, adjusting for creatinine, age, sex, and body mass index, infants with higher urinary perchlorate, nitrate or thiocyanate had higher urinary TSH. With all three modeled, children with higher nitrate and thiocyanate had higher TSH, but higher perchlorate was associated with TSH only in children with low iodide. Unexpectedly, exposure to the three chemicals was generally associated with higher T₄.

Conclusions

The association of perchlorate exposure with increased urinary TSH in infants with low urinary iodide is consistent with previous findings. Higher thiocyanate and nitrate exposure were also associated with higher TSH in infants.     

Age of Greatest Susceptibility to Childhood Lead Exposure: A New Statistical Approach

Background

Susceptibility to lead toxicity is often assumed to be greatest during early childhood (e.g., 2 years of age), but recent studies suggest that blood lead concentrations (BPb) taken at 5–7 years of age are more strongly associated with IQ.

Objective

We aimed to determine the age of greatest susceptibility to lead exposure using an innovative statistical approach that avoids the problem of correlated serial BPb measurements.

Methods

We analyzed two cohorts of children that were followed from infancy to 6 years of age in Rochester, New York (n = 211), and Cincinnati, Ohio (n = 251). Serial BPb levels were measured and IQ tests were done when children were 6 years of age. After adjustment for relevant covariates, the ratio of 6-year BPb to 2-year BPb was added to the multiple regression model to test whether the pattern of BPb profiles during childhood had additional effect on IQ.

Results

The ratio of BPb at 6 years to the BPb at 2 years showed a strong effect on IQ (p < .001) when added to the multiple regression model that included the average childhood BPb. IQ decreased by 7.0 points for children whose BPb at 6 years of age was 50% greater than that at 2 years compared with children whose 6-year BPb was 50% less than their 2-year BPb. Similarly, criminal arrest rates were a factor of 3.35 higher for those subjects whose 6-year BPb was 50% higher than their 2-year BPb.

Conclusions

We conclude that 6-year BPb is more strongly associated with cognitive and behavioral development than is BPb measured in early childhood.     

Prenatal exposure to perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) and maternally reported developmental milestones in infancy

Background

Perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) are fluorinated organic compounds present in the general population at low concentrations. Animal studies have shown that they may affect neuromuscular development at high concentrations.

Objectives

We investigated the association between plasma levels of PFOS and PFOA in pregnant women and motor and mental developmental milestones of their children.

Methods

We randomly selected 1,400 pairs of pregnant women and their children from the Danish National Birth Cohort. PFOS and PFOA were measured in maternal blood samples taken in early pregnancy. Apgar score was abstracted from the National Hospital Discharge Register in Denmark. Developmental milestones were reported by mothers using highly structured questionnaires when the children were around 6 months and 18 months of age.

Results

Mothers who had higher levels of PFOA and PFOS gave birth to children who had similar Apgar scores and reached virtually all of the development milestones at the same time as children born to mothers with lower exposure levels. Children who were born to mothers with higher PFOS levels were slightly more likely to start sitting without support at a later age.

Conclusion

We found no convincing associations between developmental milestones in early childhood and levels of PFOA or PFOS as measured in maternal plasma early in pregnancy.     

Short-Term Effects of Air Pollution on Wheeze in Asthmatic Children in Fresno,California

Background

Although studies have demonstrated that air pollution is associated with exacerbation of asthma symptoms in children with asthma, little is known about the susceptibility of subgroups, particularly those with atopy.

Objective

This study was designed to evaluate our a priori hypothesis that identifiable subgroups of asthmatic children are more likely to wheeze with exposure to ambient air pollution.

Methods

A cohort of 315 children with asthma, 6–11 years of age, was recruited for longitudinal follow-up in Fresno, California (USA). During the baseline visit, children were administered a respiratory symptom questionnaire and allergen skin-prick test. Three times a year, participants completed 14-day panels during which they answered symptom questions twice daily. Ambient air quality data from a central monitoring station were used to assign exposures to the following pollutants: particulate matter ≤ 2.5 μm in aerodynamic diameter, particulate matter between 2.5 and 10 μm in aerodynamic diameter (PM_10–2.5), elemental carbon, nitrogen dioxide (NO₂), nitrate, and O₃.

Results

For the group as a whole, wheeze was significantly associated with short-term exposures to NO₂ [odds ratio (OR) = 1.10 for 8.7-ppb increase; 95% confidence interval (CI), 1.02–1.20] and PM_10–2.5 (OR = 1.11 for 14.7-μg/m³ increase; 95% CI, 1.01–1.22). The association with wheeze was stronger for these two pollutants in children who were skin-test positive to cat or common fungi and in boys with mild intermittent asthma.

Conclusion

A pollutant associated with traffic emissions, NO₂, and a pollutant with bioactive constituents, PM_10–2.5, were associated with increased risk of wheeze in asthmatic children living in Fresno, California. Children with atopy to cat or common fungi and boys with mild intermittent asthma were the subgroups for which we observed the largest associations.     

Urinary porphyrin excretion in children is associated with exposure to organochlorine compounds

Background

Hexachlorobenzene (HCB) and other organochlorines induce porphyria cutanea tarda (PCT) in animal studies. Evidence in humans, however, is contradictory. In neonates and adults from a population historically highly exposed to HCB (Flix, Catalonia, Spain), no relation with PCT or with porphyrin excretion was found.

Objectives

We aimed to analyze the association between urinary porphyrin excretion and exposure to HCB and other organochlorinated compounds in children 4 years of age.

Methods

Our birth cohort included all newborns from Flix and the five surrounding towns (where no airborne pollution occurred). Among the 68 children with porphyrins we measured in cord blood, 52 children 4 years of age provided blood to measure organochlorine compounds, hair for methylmercury, and urine for porphyrin excretion pattern.

Results

Quantitative porphyrin excretion was within the normal values. However, total porphyrins, coproporphyrin I (CPI), and coproporphyrin III (CPIII) adjusted to creatinine excretion increased with increasing levels of HCB, 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (p,p′-DDE), 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p,p′-DDT), and polychlorinated biphenyl congener 153 (PCB-153). We found no association with methylmercury. When we fitted multiple pollutant models, p,p′-DDE had the strongest association. We found these associations in children from both Flix and other towns, and they were independent of breast-feeding and of organochlorine and porphyrin levels at birth.

Conclusion

HCB at current levels did not induce porphyria or increase uroporphyrins. However, the increase of urinary coproporphyrins suggests an incipient toxic effect of the organochlorines, especially for p,p′-DDE, on the hepatic heme-synthesis pathway that differs from the major effects seen in PCT.     

Blood Mercury Concentrations in CHARGE Study Children with and without Autism

Background

Some authors have reported higher blood mercury (Hg) levels in persons with autism, relative to unaffected controls.

Objectives

We compared blood total Hg concentrations in children with autism or autism spectrum disorder (AU/ASD) and typically developing (TD) controls in population-based samples, and determined the role of fish consumption in differences observed.

Methods

The Childhood Autism Risk from Genetics and the Environment (CHARGE) Study enrolled children 2–5 years of age. After diagnostic evaluation, we analyzed three groups: AU/ASD, non-AU/ASD with developmental delay (DD), and population-based TD controls. Mothers were interviewed about household, medical, and dietary exposures. Blood Hg was measured by inductively coupled plasma mass spectrometry. Multiple linear regression analysis was conducted (n = 452) to predict blood Hg from diagnostic status controlling for Hg sources.

Results

Fish consumption strongly predicted total Hg concentration. AU/ASD children ate less fish. After adjustment for fish and other Hg sources, blood Hg levels in AU/ASD children were similar to those of TD children (p = 0.75); this was also true among non-fish eaters (p = 0.73). The direct effect of AU/ASD diagnosis on blood Hg not through the indirect pathway of altered fish consumption was a 12% reduction. DD children had lower blood Hg concentrations in all analyses. Dental amalgams in children with gum-chewing or teeth-grinding habits predicted higher levels.

Conclusions

After accounting for dietary and other differences in Hg exposures, total Hg in blood was neither elevated nor reduced in CHARGE Study preschoolers with AU/ASD compared with unaffected controls, and resembled those of nationally representative samples.     

Hydroxylated metabolites of the polybrominated diphenyl ether mixture DE-71 are weak estrogen receptor-alpha ligands

Background

Polybrominated diphenyl ethers (PBDEs) are widely found in the environment and are suspected endocrine disruptors. We previously identified six hydroxylated metabolites of PBDE (OH-PBDEs) in treated mice.

Objective

We tested the hypothesis that OH-PBDEs would interact with and alter activity of estrogen receptor-α (ER-α).

Methods

We tested estrogenicity using two assays: ³H-estradiol (³H-E₂) displacement from recombinant ER-α and induction of reporter gene (ERE-luciferase) in cultured cells. We incubated the PBDE mixture DE-71 with rat liver microsomes and tested the resultant metabolite mixture for estrogenic activity. We also determined relative estrogenic potential of individual hydroxylated PBDE congeners.

Results

Reporter gene activity was increased by DE-71 that had been subjected to microsomal metabolism. DE-71 did not displace E₂ from ER-α, but all six of the OH-PBDE metabolites did. para-Hydroxylated metabolites displayed a 10- to 30-fold higher affinity for ER-α compared with ortho-hydroxylated PBDEs, and one produced a maximal effect 30% higher than that produced by E₂. Coadministration of E₂ and DE-71, or certain of its metabolites, yielded reporter activity greater than either chemical alone. Two ortho-OH-PBDEs were antiestrogenic in the reporter assay.

Conclusions

The observations—that the DE-71 mixture did not displace ³H-E₂ from ER-α while the hydroxylated metabolites did—suggest that the weak estrogenic effects of DE-71 are due to metabolic activation of individual congeners. However, the behavior of DE-71 and its metabolites, when co-administered with E₂, suggest a secondary, undetermined mechanism from classical ER-α activation.     

Risk of Asthmatic Episodes in Children Exposed to Sulfur Dioxide Stack Emissions from a Refinery Point Source in Montreal,Canada

Background

Little is known about the respiratory effects of short-term exposures to petroleum refinery emissions in young children. This study is an extension of an ecologic study that found an increased rate of hospitalizations for respiratory conditions among children living near petroleum refineries in Montreal (Canada).

Methods

We used a time-stratified case–crossover design to assess the risk of asthma episodes in relation to short-term variations in sulfur dioxide levels among children 2–4 years of age living within 0.5–7.5 km of the refinery stacks. Health data used to measure asthma episodes included emergency department (ED) visits and hospital admissions from 1996 to 2004. We estimated daily levels of SO₂ at the residence of children using a) two fixed-site SO₂ monitors located near the refineries and b) the AERMOD (American Meteorological Society/Environmental Protection Agency Regulatory Model) atmospheric dispersion model. We used conditional logistic regression to estimate odds ratios associated with an increase in the interquartile range of daily SO₂ mean and peak exposures (31.2 ppb for AERMOD peaks). We adjusted for temperature, relative humidity, and regional/urban background air pollutant levels.

Results

The risks of asthma ED visits and hospitalizations were more pronounced for same-day (lag 0) SO₂ peak levels than for mean levels on the same day, or for other lags: the adjusted odds ratios estimated for same-day SO₂ peak levels from AERMOD were 1.10 [95% confidence interval (CI), 1.00–1.22] and 1.42 (95% CI, 1.10–1.82), over the interquartile range, for ED visits and hospital admissions, respectively.

Conclusions

Short-term episodes of increased SO₂ exposures from refinery stack emissions were associated with a higher number of asthma episodes in nearby children.     

Long-Term Traffic-Related Exposures and Asthma Onset in Schoolchildren in Oslo,Norway

Background

Whether there is a causal relation between long-term exposure to traffic and asthma development is so far not clear. This may be explained by inaccurate exposure assessment.

Objective

We investigated the associations of long-term traffic-related exposures with asthma onset assessed retrospectively and respiratory symptoms in 9- to 10-year-old children.

Methods

We collected information on respiratory outcomes and potential confounding variables by parental questionnaire in 2,871 children in Oslo. Nitrogen dioxide exposure was assessed by the EPISODE dispersion model and assigned at updated individual addresses during lifetime. Distance to major road was assigned at birth address and address by date of questionnaire. Cox proportional hazard regression and logistic regression were used.

Results

We did not find positive associations between any long-term traffic-related exposure and onset of doctor-diagnosed asthma. An interquartile range (IQR) increase of NO₂ exposure before asthma onset was associated with an adjusted risk ratio of 0.82 [95% confidence interval (CI), 0.67–1.02]. Handling early asthma cases (children < 4 years of age) with recovery during follow-up as noncases gave a less negative association. The associations for late asthma onset (≥ 4 years of age) were positive but not statistically significant. For current symptoms, an IQR increase of previous year’s NO₂ exposure was associated with adjusted odds ratios of 1.01 (95% CI, 0.83–1.23) for wheeze, 1.10 (95% CI, 0.79–1.51) for severe wheeze, and 1.01 (95% CI, 0.84–1.21) for dry cough.

Conclusions

We were not able to find positive associations of long-term traffic-related exposures with asthma onset or with current respiratory symptoms in 9- to 10-year-old children in Oslo.