ARTICLE. Child Neurodevelopmental Outcome and Maternal Occupational Exposure to Solvents

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1 ARTICLE Child Neurodevelopmental Outcome and Maternal Occupational Exposure to Solvents Dionne Laslo-Baker, MSc; Maru Barrera, PhD; Dafna Knittel-Keren, BSc; Eran Kozer, MD; Jacob Wolpin, PhD; Sohail Khattak, MD; Richard Hackman, MD; Joanne Rovet, PhD; Gideon Koren, MD, FABMT, FRCPC Background: Many women of reproductive age are employed in industries involving exposure to organic solvents. Animal toxicological studies and human case reports demonstrate that high exposure to solvents causes neurodevelopmental toxicity in exposed offspring. Data from occupationally exposed women and their children are few. Objective: To compare the cognitive, language, and motor performance and the behavioral achievements of children whose mothers were exposed occupationally to organic solvents during pregnancy with those of a matched unexposed control group. Participants: Thirty-two pregnant women occupationally exposed to organic solvents were recruited during pregnancy and followed up. Their offspring (age range, 3-9 years) were tested for cognitive functioning (IQ), language, visual-motor functioning, and behavioral functioning and were compared with a matched unexposed control group that was recruited and tested in a similar manner. Examiners were blinded to the exposure status. Results: Mothers occupationally exposed to organic solvents did not differ significantly from matched controls in demographic variables. After controlling for potential confounding because of maternal IQ and maternal education, children exposed in utero to organic solvents obtained lower scores on subtests of intellectual, language, motor, and neurobehavioral functioning. Conclusions: In utero exposure to organic solvents is associated with poorer performance on some specific subtle measures of neurocognitive function, language, and behavior. Reducing exposure in pregnancy is merited until more refined risk assessment is possible. Further studies that address exposure to specific solvents, dose, and gestational timing of exposure are needed. Arch Pediatr Adolesc Med. 2004;158: Author Affiliations: Motherisk Program and Division of Clinical Pharmacology and Toxicology (Mss Laslo-Baker and Knittel-Keren and Drs Kozer, Wolpin, Hackman, Khattak, and Koren) and Department of Psychology (Drs Barrera and Rovet), The Hospital for Sick Children, and University of Toronto (Ms Laslo-Baker and Drs Barrera, Rovet, and Koren), Toronto, Ontario; and Departments of Medicine and Pediatrics, The University of Western Ontario, London, Ontario (Dr Koren). ORGANIC SOLVENTS ARE one of the most prevalent sources of workplace chemical exposure reported by pregnant women, 1,2 and data regarding the potential neurodevelopmental toxicity of this common exposure are few. The acute central nervous system toxicity is well described, and there are case reports of exposed mothers who abused solvents during pregnancy ( sniffers ) and delivered infants with developmental delay or birth defects. 3 In addition, animal toxicological studies demonstrate that high exposures to solvents such as toluene in pregnant rodents can impair neurobehavioral development in their offspring. 4 Less clear is the effect of long-term lower-level exposures encountered by pregnant women in occupational settings. There are myriad types of organic solvents, but they share chemical properties of high volatility and high vapor pressure, which pose an inhalation exposure risk, and they are lipid soluble and can easily penetrate the skin. Workplace environments where solvents are used include manufacturing and industry jobs involving painting and plastic adhesives, nail salons, dry-cleaning operations, and medical laboratories. One previous published epidemiological study 5 of occupationally exposed pregnant women looked at neurocognitive functioning in children between the ages of 3 and 4 years whose mothers were exposed to 1 of several types of organic solvents at some time during pregnancy. Using only the McCarthy scales, the results indicated no significant cognitive differences between the exposed and unexposed groups. The present study was designed to evaluate a comprehensive set of 956

2 neurodevelopmental outcomes in children born to women with occupational exposure to solvents in pregnancy, compared with a group of children whose mothers did not experience this exposure. METHODS STUDY SUBJECTS The study subjects were selected from children of mothers who were counseled through the Motherisk Program from 1989 to The Motherisk Program is an information and counseling service for women and their health professionals on the risk of drugs, chemicals, radiation, and infection during pregnancy and lactation. During the study period, the Motherisk Program counseled more than mothers. Women exposed occupationally to organic solvents were invited during the index pregnancy to participate in a follow-up study. They were eligible if their exposure included at least 8 weeks of pregnancy and commenced in the first trimester, although we expected that most of the women would have longer exposures because of the occupational nature of this exposure. None of the women or control subjects were exposed to lead or mercury at work or at home. In addition, they had to have answered negatively to questions regarding exposure to alcohol, drugs of abuse, teratogenic drugs, and heavy occupational lifting during their pregnancy. They were not included if they had been recruited to participate in a similar study, if child abuse issues were reported, or if they failed to show for scheduled visits, despite attempts at repeated scheduling. The eligible and available exposed mothers were matched to control mothers identified from those who were counseled by the Motherisk Program regarding nonteratogenic exposures (eg, acetaminophen and dental x-rays). A control mother was selected for each exposed mother based on similarity to the exposed mother in terms of maternal age (within 5 years), child age (within 8 months), child sex, socioeconomic status (divided into 7 categories in $ increments of annual family income), and reported cigarette use during pregnancy. EXPOSURE ASSESSMENT Details about the organic solvent exposure were recorded once prenatally and twice postnatally. The initial information was obtained during pregnancy, at the time of the mother s first contact with the Motherisk Program. This information was confirmed when the study coordinator (D.K.-K.) contacted these mothers to discuss continued participation in the study. The physician (R.H. or E.K.) obtained a second confirmation of exposure details at the time of the assessment. The recorded information included specific type of organic solvents involved in the exposure, type of occupational setting, duration of exposure in pregnancy, any adverse symptoms, type of protective gear used, and other safety features, including ventilation fans in the work environment. OUTCOME ASSESSMENT Each child and mother (study subjects and controls) were administered an age-appropriate battery of neurodevelopmental and cognitive functioning tests. In addition, each mother completed 2 questionnaires that assessed behavioral functioning in her child. Following the assessment, each mother was mailed a research summary report of the results of the assessment. Appropriate referrals were made if problems became evident during the assessment. Because, to our knowledge, this is the first comprehensive study on organic solvents, a wide range of tests was applied that aimed at capturing potential effects on different neurodevelopmental domains of cognitive and motor functioning, language, and behavior. Children s cognitive abilities (IQ) were measured by using the Wechsler Preschool and Primary Scale of Intelligence 6 for children between the ages of 3 years and 5 years 11 months, and the Wechsler Intelligence Scale for Children 7 for children between the ages of 6 years and 8 years 11 months. Language development was assessed by the Preschool Language Scale 8 for children between the ages of 3 years and 5 years 11 months, and the Clinical Evaluation of Language Fundamentals 9 for children between the ages of 6 years and 8 years 11 months. Children s motor development was measured by using the Beery- Buktenica Developmental Test of Visual-Motor Integration. 10 Manipulative dexterity and visual-motor coordination were measured by using the Grooved Pegboard Test. 11 Children s behavioral functioning was measured by using the Child Behavior Checklist, 12,13 Conner s Rating Scale Revised, 14 and Behavioral Style Questionnaire, 15 which are questionnaires that were completed by the mother. Maternal cognitive functioning was measured by using the Wechsler Abbreviated Scale of Intelligence. 16 Each of these tests has been well standardized, is widely used in clinical and research settings, and has good reliability and validity. All subsets of the mentioned tests were used. DATA ANALYSIS The sample size was sufficient to detect a medium effect size (ie, 7-8 points of IQ difference) between the groups with a power of 80% and =.05. A preliminary analysis comparing the groups on potential confounders was conducted. Multiple linear regression analysis was used to evaluate neurodevelopmental outcome scores in relation to solvent exposure, controlling for important potential confounders. The role of behavioral problems as a confounder or an outcome in the causal pathway between solvent exposure and neurodevelopmental outcome was also explored. RESULTS Thirty-two exposed mother-child pairs and 32 matched control pairs were recruited for the study. Table 1 presents sample inclusion and exclusion details, including loss to follow-up because of refusal, brief chemical exposure, fetal loss, failure to come to testing, and other reasons. The exposed group of 32 mothers did not differ from their controls in family demographics and maternal characteristics, including gravidity, parity, and vitamin use. Table 2 lists the occupations of the study and control women. Fifty-four of the women (85%) were white. Maternal verbal IQ tended to be lower among women exposed to organic solvents (104 [95% confidence interval {CI}, ] vs 110 [95% CI, ]). The children in the 2 groups did not differ in birth weight, gestational age, or age at attaining developmental milestones (Table 3). None had major malformations or experienced neurological deficits. The 2 groups had similar length of breastfeeding. Mothers in the exposed group reported being exposed to 78 organic solvents (Table 4) between 1 and 40 hours per week (mean±sd, 24±15 hours) and between 8 and 40 weeks (mean±sd, 32±10 weeks) during their pregnancy. All were exposed dur- 957

3 Table 1. Sample Exclusion and Inclusion Details Among 226 Mothers Exposed to Organic Solvents Who Contacted the Motherisk Program During 1989 to 1998 Detail No. Total No. of mothers who were not contacted 82 Lost to follow-up (ie, number not in service or 66 no listing in telephone directory) Not living in Canada 7 Maternal thyroid condition 2 Mother exposed to other chemicals in addition 3 to organic solvents Physician contacted the Motherisk Program to obtain 2 information for patient who can no longer be contacted Binge drinking during pregnancy 2 Mother called to obtain general information, 2 not specifically regarding a pregnancy Mothers who refused to participate 50 Total No. of mother-child pairs who participated 32 and were included in study Excluded following testing as exposure levels too low 26 Miscarriage, stillbirth, or child death 9 Family lived too far away and was unable to travel 6 to The Hospital for Sick Children to participate Family did not show for appointment and could 6 not be rescheduled A control match could not be found 3 Maternal hyperthyroid condition not reported 2 at initial contact with the Motherisk Program or during initial call from research coordinator Engaged in heavy lifting at work 2 Child diagnosed as having severe autism 1 Traumatic insult during pregnancy (severe fall) 1 Mother could not comprehend English at sufficient 1 level for inclusion Marijuana use during pregnancy 1 Mother declined participation as child diagnosed 1 as having cystic fibrosis Child excluded because of physical abuse 1 reported at time of assessment Table 2. List of Occupations for Exposed and Control Groups* Exposed Group Control Group Interior design consultant Coordinator for pharmaceutical company Painter Stay-at-home mother (n = 4) Laboratory technician (n = 8) Accountant Hair stylist or color technician Circulation manager Factory worker (n = 4) Nurse (n = 2) Industrial laundry worker Systems training manager Chemical technologist Office worker Photograph laboratory work (n = 2) Daycare teacher Graphic designer (n = 3) Schoolteacher (n = 5) Conservator (n = 2) Payroll administrator Salon receptionist Social worker (n = 2) Science teacher Secretary Aesthetician Sales manager (n = 2) Funeral director or embalmer (n = 2) Law clerk Chemist Legal secretary Carpenter Receptionist or dental assistant Electrical company worker Computer programmer Physician s assistant Marketing assistant Bookkeeper Financial planner Lawyer *n = 1 for all unless otherwise noted. ing most of the first trimester of pregnancy. The exposed mothers reported a high level of protective equipment use. The primary outcome measures were IQ and language scores for the 2 groups. The verbal IQ scores were significantly lower in the exposed group than in the control group (108 [95% CI, ] vs 116 [95% CI, ]), as were the full-scale IQ scores (108 [95% CI, ] vs 114 [95% CI, ]). There were no significant differences in performance IQ between the groups. Children exposed in utero to organic solvents displayed a tendency toward lower scores in expressive language (109 [95% CI, ] vs 116 [95% CI, ]), total language (111 [95% CI, ] vs 117 [95% CI, ]), and receptive language (112 [95% CI, ] vs 117 [95% CI, ]) than children in the control group. In multiple regression analyses, achievements in cognitive subscales, language, motor, and behavioral scores served as dependent variables, while maternal education, maternal full-scale IQ, exposure status, and behavioral scores (Child Behavior Checklist) were the independent variables (Table 5). The analyses of digit span (which measures processing speed and memory), information, vocabulary, and recalling sentences scores, as well as scores on the grooved pegboard (which measures dexterity and visual-motor coordination) and Conner s hyperactivity/ impulsivity revealed that exposure to organic solvents was the only factor accounting for the variance in these scores. For measures of visual-motor coordination, behavioral scores also contributed to the variance. A second series of multiple regression analyses was conducted to clarify whether child behavior could have affected the following dependent variables: child IQ, language, motor functioning, and behavioral functioning. Specifically, the independent variables were maternal IQ matched to the child s type of IQ being measured (ie, maternal full-scale IQ with child s full-scale IQ) and to the Child Behavior Checklist score when the dependent variable was not the Child Behavior Checklist score (in which case the child s full-scale IQ was used as an independent variable) (Table 6). The results corroborated the previous model, showing that exposure to organic solvents was the only independent variable adversely affecting motor functioning, behavior, attention, and hyperactivity. Maternal IQ accounted for the global variance of the child s IQ and language. Within the exposed group, there was no relationship between the length of gestational exposure to organic solvent, the total hours of exposure in pregnancy, and any of the neurodevelopmental test scores. COMMENT The results of this study suggest some adverse fetal effects of occupational exposure to organic solvents dur- 958

4 Table 3. Comparison of Child Characteristics Between Those Exposed to Organic Solvents vs Matched Unexposed Control Subjects* Characteristic Exposed Unexposed P Value Child age at testing, mo 69.7 ± ± Child sex 1.6 ± ± Maternal age at child s birth, y 30.6 ± ± Maternal age at testing, y 36.5 ± ± Maternal education 3.4 ± ± Socioeconomic status 2.8 ± ± Length of breastfeeding, mo 7.0 ± ± Apgar score at 1 min 8.6 ± ± Apgar score at 5 min 9.4 ± ± Birth weight, kg 3.3 ± ± Gestational age, wk 39.4 ± ± Height at time of testing, cm ± ± Weight at time of testing, kg 23.1 ± ± Head circumference at 51.7 ± ± time of testing, cm Milestones First smile, wk 7.2 ± ± Lifted head, wk 9.5 ± ± Sat, wk 25.0 ± ± Crawled, wk 37.6 ± ± Stood, wk 35.5 ± ± First word, wk 36.1 ± ± Walked, wk 47.3 ± ± *Data are given as mean ± SD unless otherwise indicated. Female, 1; male, 2. Completed up to elementary school, 1; high school, 2; some college, 3; university degree, 4; and graduate school, 5. Annual family income $ to $30 000, 1; greater than $ to $50 000, 2; and greater than $50 000, 3. ing pregnancy as measured by neurocognitive, behavioral, and motor coordination measures. Exposed children performed at a lower level than control children in subtests that measure short-term auditory memory, general verbal information, and attention. Furthermore, children who were exposed to organic solvents in utero showed reduced ability in recalling sentences, even when their global scores were within the normal range. Maternal IQ appears to be a critical factor only when considering global cognitive functioning and language. The results of this study are consistent with animal toxicity data 5 and recent findings with young children 17,18 suggesting differences between exposed and unexposed offspring in language and graphomotor functioning, visual acuity, and color vision. Earlier work with children 5 demonstrated no significant differences in global measures of neurocognitive functioning, which is consistent with our global findings. However, these authors did not examine specific subtests for more subtle cognitive and language differences, motor activity, or behavior. These results suggest that there may be a characteristic pattern of adverse effects associated with organic solvent exposure in the cognitive and language domains, within areas of recall, attention, and language. Moreover, our results suggest that there may be differences in motor and behavioral functioning as well. Children exposed to organic solvents during pregnancy Table 4. Common Organic Solvents to Which the Women Were Occupationally Exposed* Chemical No. of Women Exposed Toluene 12 Xylene 10 Ethanol 7 Acetone 6 Methanol 5 Isopropanol 4 Mineral spirits 4 Ethyl acetate 4 Isopropyl alcohol 4 Benzalkonium chloride 3 Acrylic resin 3 Methylene chloride 3 Hexane 3 Trichloroethylene 3 Phenol 2 Propylene glycol 2 Monomethyl ether acetate 2 Triethylene glycol 2 Benzyl alcohol 2 Napthoxypoly-oxyethylene 2 1,1,1-Trichloroethane 2 Methyl-ethyl ketone 2 Dichloromethane 2 t-butanol 2 *Some mothers were exposed to more than 1 solvent. displayed inferior manipulative dexterity and complex visual-motor coordination and greater inattention and hyperactivity. Therefore, exposure to organic solvents appears to be the critical variable for more subtle differences in verbal IQ, visual-motor coordination, and behaviors characterized by inattention and hyperactivity. Each of these areas, combined or on its own, may pose challenges to these children academically and socially. In addition, if children are not successful in facing these challenges during their early school years, they may risk not achieving their full potential at school, limiting their career choices in later life. Strengths of this study include an ability to identify pregnant women exposed to toxicants in pregnancy, as well as to collect other relevant important information such as maternal IQ, health status, and socioeconomic level. 19 Our sample size was sufficiently large to detect a medium effect size in IQ (ie, 7-8 points). The important confounding effect of maternal IQ in other studies that address the effect of in utero toxicant exposure on neurodevelopment and child cognitive and behavioral function was observed and controlled for in our data. A potential pitfall of all epidemiological studies dealing with the reproductive risks of organic solvent exposure is the multitude of chemicals used simultaneously by some of these women (eg, laboratory technicians). Yet, there are physicochemical and toxicological similarities that make lumping of these compounds biologically plausible. In our series, women were exposed to numerous compounds (Table 4), and larger studies will be needed to sort out which specific chemicals pose a risk to pregnant women and their fetus. Methodologi- 959

5 Table 5. Multiple Linear Regression Analysis of Different Neurobehavioral Test Results Showing Children Exposed to Organic Solvents vs Unexposed After Adjustment for Maternal IQ and Maternal Education* Organic Solvents Criterion Exposed Unexposed Value P Value Child WISC full-scale IQ ± ± Child WISC verbal IQ ± ± Child WISC performance IQ ± ± Total language score ± ± Receptive language score ± ± Expressive language score ± ± Recalling sentences standard score ± ± CELF recalling sentences standard score ± ± Dominant hand grooved pegboard score 0.96 ± ± Nondominant hand grooved pegboard score 0.46 ± ± Behavioral Style Questionnaire activity level 3.86 ± ± CBCL somatizing score ± ± CBCL internalizing score ± ± CBCL total score ± ± Conner hyperactivity/impulsivity 8.49 ± ± Conner DSM-IV diagnosis, hyperactivity ± ± Conner DSM-IV score ± ± Abbreviations: CBCL, Child Behavior Checklist; CELF, Clinical Evaluation of Language Fundamentals; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; WISC, Wechsler Intelligence Scale for Children. *Data are given as adjusted mean ± SE unless otherwise indicated. Unless otherwise indicated, all criteria are evaluated at covariates appearing in the model maternal full-scale IQ and maternal education. Evaluated at covariates appearing in the model maternal verbal IQ and maternal education. Evaluated at covariates appearing in the model maternal performance IQ and maternal education. Table 6. Multiple Linear Regression Analysis of Different Neurobehavioral Test Results Showing Children Exposed to Organic Solvents vs Unexposed After Adjustment for Maternal IQ, Maternal Education, and Child Behavior Measured by Child Behavior Checklist (CBCL)* Organic Solvents Criterion Exposed Unexposed Value P Value Child WISC full-scale IQ ± ± Child WISC full-scale IQ ± ± Child WISC verbal IQ ± ± Total language score ± ± Receptive language score ± ± Expressive language score ± ± WISC digit span subtest ± ± WPPSI information ± ± WPPSI vocabulary ± ± CELF recalling sentences standard score ± ± Dominant hand grooved pegboard score 1.07 ± ± Nondominant hand grooved pegboard score 0.55 ± ± CBCL internalizing score ± ± Conner DSM-IV diagnosis, hyperactivity ± ± Abbreviations: CELF, Clinical Evaluation of Language Fundamentals; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; WISC, Wechsler Intelligence Scale for Children; WPPSI, Wechsler Preschool and Primary Scale of Intelligence. *Data are given as adjusted mean ± SE unless otherwise indicated. Unless otherwise indicated, all criteria are evaluated at covariates appearing in the model maternal full-scale IQ and CBCL total score. Evaluated at covariates appearing in the model maternal verbal IQ and CBCL total score. Evaluated at covariates appearing in the model maternal full-scale IQ and child WISC full-scale IQ. cally, this situation may resemble the reproductive risks of environmental tobacco smoke, in which women are exposed to 1400 different toxins and the specific culprits have not yet been elucidated. However, with environmental tobacco smoke, these toxins are different chemically and toxicologically. The lack of a dose-response curve in our study may reflect a small sample, as the study was not powered on this aspect. Our study is also underpowered to elucidate effects during critical windows of development of the central nervous system. Our study subjects did not differ from their controls in occupational or domestic exposure to lead and mercury, which are potential confounders for central nervous system development. 15 Although we did not track 960

6 What This Study Adds Previous studies documented the toxic effect of organic solvents on the adult brain. In animals, these compounds were shown to affect offspring through maternal exposure. Human data are sparse. This study shows for the first time, to our knowledge, in a systematic way that in utero exposure to organic solvents is associated with poor performance on some specific subtle measures of neurocognitive function, language, and behavior. indexes of anemia in these children, they were appropriate for their ages nutritionally and physically. Our sample included women who were motivated to call a free teratogen information service. They reported a high level of protective equipment use. Their exposure and use of protective equipment may be greater or less than those of other solvent-exposed women. Nevertheless, in these women we observed subtle effects on neurocognitive and behavioral outcomes that would support minimizing maternal (and thus fetal) exposure to solvents during pregnancy until more definitive risk assessment is possible. Strategies include appropriate protective gear, ventilation, and consideration of changed work duties or location. Further evaluation of the potential neurodevelopmental toxicity of solvent exposure is merited. Studies designed to clarify exposure effects in regard to specific solvents, dose levels, and timing of exposure will be most valuable. Accepted for Publication: May 13, Correspondence: Gideon Koren, MD, FABMT, FRCPC, Motherisk Program and Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada (gkoren@sickkids.ca). Funding/Support: This study was supported by a grant from Physician Services Inc, Toronto. Dr Laslo-Baker received a doctoral research award from the Canadian Institutes of Health Research (CIHR), Ottawa, Ontario. Dr Kozer received a fellowship from the Research Training Centre, The Hospital for Sick Children. Dr Koren is a senior scientist of CIHR and holder of the Research Leadership in Better Pharmacotherapy During Pregnancy and Lactation and The Ivey Chair in Molecular Toxicology, The University of Western Ontario, London, Ontario. REFERENCES 1. Organic Solvent Neurotoxicity. Washington, DC: National Institute for Occupational Safety and Health, US Dept of Health and Human Services; Current Intelligence Bulletin Bentur Y, Koren G. The three most common occupational exposures reported by pregnant women: an update. Am J Obstet Gynecol. 1991;165: Scheerer JJ, Chudley AE. Solvent abuse in pregnancy: a perinatal perspective. J Obstet Gynaecol Can. 2002;24: Gospe SK Jr, Zhou SS. Toluene abuse embryopathy: longitudinal neurodevelopmental effects of prenatal exposure to toluene in rats. Reprod Toxicol. 1998; 12: Eskenazi B, Gaylord L, Bracken MB, Brown D. In utero exposure to organic solvents and human neurodevelopment. Dev Med Child Neurol. 1988;30: Wechsler D. Manual for the Wechsler Preschool and Primary Scale of Intelligence. New York, NY: Psychological Corp; Wechsler D. Manual for the Wechsler Intelligence Scale for Children. 3rd ed. New York, NY: Psychological Corporation; Zimmerman IL, Steiner VG, Evatt Pond RE. Preschool Language Scale. 3rd ed. New York, NY: Psychological Corporation; Semel E, Wiig EH, Secord WA. Clinical Evaluation of Language Fundamentals. 3rd ed. New York, NY: Psychological Corporation; Beery KE. Manual for the Beery-Buktenica Developmental Test of Visual-Motor Integration. Parsippany, NJ: Modern Curriculum Press; Grooved Pegboard Test. Lafayette, Ind: Lafayette Instrument; Achenbach TM. Manual for the Child Behavior Checklist/2-3 and 1992 Profile. Burlington: Dept of Psychiatry, University of Vermont; Achenbach TM. Manual for the Child Behavior Checklist/4-18 and 1991 Profile. Burlington: Dept of Psychiatry, University of Vermont; Conner CK. Manual for the Conner s Rating Scale Revised. Toronto, Ontario: Multi-Health Systems Inc; McDevitt SC, Carey WB. The measurement of temperament in 3-7 year old children. J Child Psychol Psychiatry. 1978;19: Wechsler D. Manual for the Wechsler Abbreviated Scale of Intelligence. New York, NY: Psychological Corp; Till C, Koren G, Rovet JF. Prenatal exposure to organic solvents and child neurobehavioral performance. Neurotoxicol Teratol. 2001;23: Till C, Westall CA, Rovet JF, Koren G. Effects of maternal occupational exposure to organic solvents on offspring visual functioning: a prospective controlled study. Teratology. 2001;64: Tong IS, Lu Y. Identification of confounders in the assessment of the relationship between lead exposure and child development. Ann Epidemiol. 2001;11: