Tih348391 703.710

Toxicology and Industrial Health25(9-10) 703–710 ª The Author(s) 2009Reprints and permission: http://www.
sagepub.co.uk/journalsPermission.navDOI: 10.1177/0748233709348391tih.sagepub.com Kaye H Kilburn, Jack D Thrasher and Nina B Immers AbstractIncreased prevalence of the autism spectrum disorders (ASD) and the failure to find genetic explanations haspushed the hunt for environmental causes. These disorders are defined clinically but lack objectivecharacterization. To meet this need, we measured neurobehavioral and pulmonary functions in eight ASDboys aged 8 to 19 years diagnosed clinically and compared them to 145 unaffected children from acommunity with no known chemical exposures. As 6 of 35 consecutive mold/mycotoxin (mold)-exposedchildren aged 5 to 13 years had ASD, we compared them to the 29 non-ASD mold-exposed children, andto the eight ASD boys. Comparisons were adjusted for age, height, weight, and grade attained in school. Theeight ASD boys averaged 6.8 abnormalities compared to 1.0 in community control boys. The six mold-exposedASD children averaged 12.2 abnormalities. The most frequent abnormality in both groups was balance,followed by visual field quadrants, and then prolonged blink reflex latency. Neuropsychological abnormalitieswere more frequent in mold-exposed than in terbutaline-exposed children and included digit symbol substitu-tion, peg placement, fingertip number writing errors, and picture completion. Profile of mood status scoresaveraged 26.8 in terbutaline-exposed, 52 in mold exposed, and 26 in unexposed. The mean frequencies of35 symptoms were 4.7 in terbutaline, 5.4 in mold/mycotoxins exposed and 1.7 in community controls.
KeywordsAutism spectral disorder, balance, blink reflex, mycotoxins, neurobehavioral tests, visual fields associated with an increased risk of autism, mostlikely due to the effects they have, which result in a Large increases in the prevalence of autism and aut- decreased ability to detoxify specific environmental ism spectrum disorders (ASD) have occurred in the toxins (Swanson et al 1998). On the other hand, the United States and United Kingdom. In the United search for environmental chemical causes of ASD States, the autism rate went from <3 to >30 per yields lead, mercury, PCBS, pesticides, and air pollu- 10,000 children in the 1970s compared to the 1990s, tion (Calderon-Garciduenas et al., 2008; Grandjean while the prevalence in the United Kingdom and Landrigan, 2006; Spzir, 2006a,b; Windham increased from <10 to about 30 per 10,000 from the et al., 2006). These authors later found evidence of 1980s compared to the 1990s. Reported rates for ASD cognitive deficits in children from air pollution.
range up to 60 to 80 per 10,000 in these two countries Recent reports have connected mold exposures with (Baxill, 2004). Recently, the CDCP announced its neurological deficits in children and adults (Crago ADDM study that showed a rate of 1 in 150 in8-year-old children in multiple areas of the UnitedStates (CDCP, Mestel 2003, Carey, 2007). The causesof ASD are unknown. Proposed single gene causes are Neuro-Test Inc., Pasadena, California, USA not convincing, except in Reye syndrome (Hertz- Picciotto et al., 2006; Muhle et al., 2004). Many single Kaye H Kilburn, Keck School of Medicine (ret.), University of nucleotide polymorphisms (SNPs) including the Southern California, 3250 Mesaloa Lane, Pasadena, CA 91107, GSTM1 null allele, GSTP1, and PON1 SNPs are Toxicology and Industrial Health 25(9-10) et al., 2003; Kilburn, 2003; Rea et al., 2003; Turner tests was administered combined with psychological measures that have also been modeled statistically A new search for neurobehavioral impairment and (Kilburn, 1998; Kilburn et al., 1998a,b). Each subject environmental causal factors in ASD was undertaken.
and/or parent recorded the frequency of 35 symptoms ASD was present in five boys whose mother had pre- scaled 1 to 10 completed a Profile of Mood States and mature labor and was given terbutaline as tocolytic other feeling states inventories and questionnaires to treatment during hospitalization. Another mother, an collect historical and exposure data.
asthmatic, had used terbutaline aerosols (Breathine)daily during her three pregnancies. Terbutaline, a beta-adrenergic agonist and a neuro-toxicant in rats, Simple (SRT) and two choice visual reaction time has caused neurochemical changes leading to neuro- (CRT) were measured from appearance to cancella- nal injury and reactive gliosis around cerebellar tion of a 10-cm block letters, A for simple and A and Purkinje cells (Owens and Sriram 1995 Rhodes S for choice (Miller et al., 1989) with a computerized et al., 2004; Zerrate et al., 2007). We postulate similar instrument (Neurotest, Inc., Pasadena, CA, USA). The action in human subjects. Six children of 35 examined lowest median score of the last 7 in each of the two for effects of mold/mycotoxins exposure had ASD.
trials of 20 was accepted for SRT and for CRT. Body This rate of 17% greatly exceeded the 0.7% frequency balance was measured with the subject standing erect of ASD in unselected children. Mold/mycotoxins with feet together (Kilburn and Warshaw, 1994). The have been associated with deficiency of growth hor- position of the head was recorded (tracked) with a mone and thyroid dysfunction by Dennis 2009 (this sound receiver from a sound-generating stylus on a symposium). Thus, we measured neurobehavioral headband (Neurotest, Inc.). Results were processed abnormalities of balance, reaction time, color dis- by a software program and expressed as mean speed crimination, concentration, recall memory, multi- of sway in cm per sec The minimal sway speed of tasking, and long-term memory in these 14 ASD chil- three consecutive 20-sec trials was counted for sway dren, utilizing testing procedures previously reported (Crago et al., 2003; Kilburn, 2003; Rea et al., 2003).
recorded the blink reflex from the orbicularis oculi muscles (Kilburn et al., 1998a,b; Shahani and Young, The objectives were to determine whether children 1972) after tapping right and left supraorbital notches with ASD following toxic exposures have decreased with a light hammer, which triggered a recording performance on standardized neurobehavioral and computer (Neurotest, Inc.). Ten firings of R-1 were pulmonary tests compared to referents. The ASD chil- averaged for mean response for each side and failures dren consisted of two groups: (1) mothers who either were recorded (Kilburn et al., 1998a,b). Color dis- received terbutaline for its tocolytic effect while preg- crimination as confusion index was measured with the nant or for therapy of the mother’s asthma and (2) desaturated D’Lanthony 15 hue test under 1000 Lux illumination (D’Lanthony, 1978) and scored by the These are hypotheses generating observations that method of Bowman (Bowman, 1982). Hearing in the should help propose and develop studies that will left and right ears was measured with standard audio- forge connections between causes and mechanisms meters (Model ML-AM Microaudiometrics; So Day- of ASDs particularly with observations in children.
tona, FL, USA) at interval frequencies of 500 to 8,000Hertz. The sum of deficits in both ears was the hearing Fourteen children, eight boys with ASD, two girlsand four boys with ASD associated with mold/myco- toxin exposure had neurobehavioral measurements Immediate or recall memory was measured with two and completed a medical history and examination.
stories from Wechsler’s Memory Scale, revised The methods have been published repeatedly since (Wechsler, 1987). Culture Fair tested non-verbal 1982 and are reviewed briefly below (Kilburn, arithmetic intelligence with designs featuring similar- 2003; Kilburn and Thornton, 1995; Kilburn et al., ity, difference, completion, and pattern recognition 1998a,b). A well-standardized group of physiological and transfer (Cattell, 1951; Cattell et al., 1941).
Culture Fair resembles Raven’s progressive matrices Table 1. Demographic and frequencies of findings in four (Raven et al., 1988). The 46-word multiple choice vocabulary test was from Jackson’s multidimensional aptitude battery (Jackson, 1985). Digit symbol substi-tution from the Wechsler Adult Intelligence Scale- revised (WAIS-R; Reitan, 1966) tested attention and integrative capacity. Information, picture completion, and similarities also from the WAIS-R (Wechsler, 1981) tested long-term (embedded or hold) memory.
Time needed to place 25 pegs in the Lafayette- slotted pegboard, and to make trails A and B were measured to assess dexterity, coordination, and decision making. Fingertip number writing measured ASD, autism spectrum disorders; POMS, profile of mood states. Abn peripheral sensation and discrimination. These were mean: average number of abnormalities per child, ChBronc %: from the Halstead-Reitan battery (Reitan, 1958, chronic bronchitis prevalence, Chem/as %: chemical hypersensitivity.
1966). Subjects’ moods were appraised by responsesto 65 terms describing feelings for the past week using were compared to their individual predicted values the Profile of Mood States (POMS; Profile of Mood and expressed as percentage predicted. Then each States, 1971/1981). Recall of the Rey 15 forms tested observed value was compared to the predicted value whether items recalled were appropriate or suggested based on the control group. The observed values out- side the confidence intervals of the predicted values examinations concentrated on cranial nerves, move- were abnormal (Kilburn et al., 1998a,b). Factors such as family income, hours of general anesthesia, POMS Respiratory flows and vital capacities were mea- score, and depression score had no significant influ- sured from a full inspiration while subjects stood and ence on the prediction equations and were excluded.
exhaled (using a nose clip) into a pneumotachy- Statistical significance was defined as p < .05.
graphic spirometer (Spirovision-3 Futuremed Gran- Abnormalities for each child and referents were ada Hills, CA, USA). This maneuver was repeated counted after assigning bilateral tests a value of 0.5 until two forced expirations agreed within 5% as per per side, for example hearing, except visual field per- ATS criteria (ATS Statement, 1987). Volume and formance, counted 1 per side and balance with eyes flows measured by a computer (Spirovision-3 Future- open and with eyes closed were scored 1 each.
med Granada Hills, CA, USA). Prediction equationsadjusted for height, age, sex, and smoking status(Miller et al., 1986). Alcohol was measured in air expired after a 15-sec breath hold using a fuel cell Eight ASD boys aged 8 to 19 were studied and com- analyzer (Alcohol Intoximeter, St. Louis, MO, USA) pared with control subjects after observations were as was carbon monoxide (Micro Smokerlyzer. Bed- adjusted for all significant factors and expressed as percentage predicted. Six ASD mold/mycotoxin (m/m)-exposed children aged 5 to 13 were similarly com-pared, Table 1. Values outside the confidence inter- vals of mean estimates were regarded and counted Scores and computed data were entered into an IBM-compatible microcomputer. Descriptive and Total abnormalities in terbutaline-exposed boys analytical computations adjusted for differences in ranged from 3 to 11, with a mean of 6.8 as compared age, education, sex, height, and weight using stepwise to 0.9 in controls. In the mold/mycotoxin ASD group, linear regression modeling that used Stata Statistical the mean was 12.2, with a range of 2 to 20 (2, 7, 10, Software version 8 (Stata Corporation, College Sta- 16, 16, and 20). There were only 2.6 abnormal tests in tion, TX, USA). These prediction equations were the 29 mold/mycotoxin non-ASD group. Profile of based on measurements of 145 school children from Mood States ranged from 7 to 64, with a mean of the neighboring state of Arizona as referents (Kilburn 27 in the terbutaline-exposed children, 52 in the et al., 1998a,b). Each child’s observed measurements mold/mycotoxin-exposed ASD children, 41 in the Toxicology and Industrial Health 25(9-10) Table 2. Abnormalities in autism spectral disorder, Picture completion was abnormal in 50% of both groups. Peg placement was abnormal in 50% of terbu-taline ASD and 34% of mold/mycotoxin ASD. Imme- diate verbal recall was abnormal in 38% and delayed verbal recall in 25%, and Culture Fair were abnormal in 25% of the terbutaline ASD boys. Only two mold/ mycotoxin children could do verbal recall and Culture Fair and results were not abnormal. Vocabulary, information, and similarities were not abnormal.
Pulmonary function tests showed small airways obstruction in 50% of terbutaline ASD and 50% of mold/mycotoxin ASD, but no decrease in vital capac- ity or in forced vital capacity in 1 sec (FEV1). Onemold/mycotoxin ASD child of 13 years had asthma mold/mycotoxin without ASD group compared to 26 Frequency of symptoms on a scale of 10 had a mean of 4.7 (range 1.3 to 4.6) in the terbutaline ASDgroup while the mean was 5.2 and (range 3.1 to 7.2) in ASD had been diagnosed in 6 of 35 (17%) children those mold/mycotoxin ASD exposed. In contrast, from families we evaluated for effects of exposure children without ASD exposed to mold/mycotoxins to molds and mycotoxins indoors in homes and had mean scores of 3.9 and unexposed children had schools from 2001 to 2007. This was 24 times the mean scores of 1.7. The specific tests are compared national estimated of ASD, which is 1 in 150 or in the ASD groups as there were few abnormalities in those exposed to mold/mycotoxins only.
Terbutaline was given intravenously to the mother of five boys (same mother four different fathers)through much of the third trimester of pregnancy to reduce uterine contractions and prevent premature Balance as speed of sway was abnormal in 88% of ter- expulsion of the fetus, tocolytic effect. The mother butaline boys and 100% in the mold/mycotoxin ASD of three boys had asthma and used terbutaline (Breathine) through each of her three pregnancies.
Visual field quadrants were abnormal in 100% of The six mothers of mold/mycotoxin-exposed ASD terbutaline boys. Only one mold/mycotoxin ASD children were not asthmatic, nor had they used terbu- child was mature enough to do visual fields, and she taline. The asthmatic mother of one subsequent ASD child who was seven years old used albuterol, a beta Blink reflex latency was abnormal in 63% of terbu- agonist similar in structure to terbutaline, repeatedly taline and 34% mold/mycotoxin ASD children.
after the 20th week of pregnancy. He had nine Reaction time was abnormal in 12% of terbutaline ASD, contrasted with while 66% with abnormal in the The two girls and four boys with mold/mycotoxin- mold/mycotoxin ASD children. Grip strength, color associated ASD averaged nine abnormalities more differentiation errors, hearing, and vibration sensitiv- than the terbutaline-exposed, with abnormal balance, being the most frequent. More of the mold/mycotoxinASD children had abnormally prolonged reactiontime, fewer had abnormal blink reflex latency and peg placement, but digit symbol substitution, picture com- Digit symbol substitution was abnormal in 50% of ter- pletion, and fingertip number writing errors were fre- butaline ASD and 66% of mold/mycotoxin ASD. Fin- quent in both groups. Only one had visual field testing gertip number writing errors was abnormal in 50% of and it was normal. Thus these two groups appeared terbutaline ASD and 66% of mold/mycotoxin ASD.
more similar than different. These numbers are small so the suggested trends need to be tested with more Slotkin et al., 2003; Zerrate et al., 2007); (4) Oxida- tive stress (Slotkin et al., 2005); (5) Alterations in Environmental factors are suggested to cause neu- signaling cascades that affect cell differentiation rodevelopmental toxicity. They include industrial (Cousin and Seidler, 2002; Slotkin et al., 2003, chemicals (Grandjean and Landrigan, 2006; Spzir, 2005); (6) Possible sensitization to the adverse effects 2006), mercury in thimerosal (Madsen et al., 2002; of organophosphate insecticides (Meyer et al., 2005); Wakefield et al., 1998) and from incinerators (Palmer (7) Probably other organ effects on heart, lens accom- et al., 2006); food additives (McCann et al, 2007); modation, liver lungs, etc. (Kudlacz et al., 1989; measles virus (Madsen et al., 2002); agriculture pesti- Rhodes et al., 2003; Thorkelsson and Loughead, cides (Roberts et al., 2007); testosterone (Baron- 1992); and (8) Serotonin receptors (5HTA, 5HT2, and Cohen, 2003, 2005); tricyclic antidepressants; and 5HT presynaptic transporter) were shown to have fluoxetine (Nulman et al., 2002). Thus, mold and increased in expression in the midbrain, brain stem, mycotoxin exposure should be added to the list of and hippocampus after administration of terbutaline neurotoxic chemicals associated with ASD as well or chlorpyrifos; males were more affected than as toxic encephalopathy. Trichothecenes and afla- females with some regional disparities in the sex toxin B1 cause inflammation and neurodegeneration selectivity between the two agents. Both chemicals of the olfactory tract of rodents (Islam et al., 2006, altered 5HT receptor-mediated cell signaling, sup- 2007; Larsson and Tjalve, 2000). Also, occupants of pressing stimulatory effects on adenyl cyclase and mold-contaminated structure develop neurotoxicity enhancing inhibitory effects. When both chemicals including neurocognitive deficits (Crago et al., were administered sequentially, the outcomes were 2003; Kilburn, 2003; Rea et al., 2003). Finally, myco- additive (Aldridge et al., 2005). Finally, neuroglia toxins are airborne in buildings and are in the sera of activation and neural inflammation have been demon- exposed occupants (see Thrasher and Crawley, 2009, strated in the brain of patients with autism (Vargas et al., 2005). The neuroinflammation is characterized b3-adrenoreceptors are predominant in human myo- by increased TGF-alpha in the cerebrospinal fluid metrium in pregnancy. Beta-adrenergic agonists, e.g.
coupled with a shift toward Th2 immunity (Cohly terbutaline, are used to control preterm labor (Rouget and Panja, 2005; Chez et al., 2007) In summation, et al., 2005). Terbutaline readily crosses the placenta during key stages of neurodevelopment, the beta- following a single intravenous (iv) dose (Bergman 2-adrenoreceptors are sensitized rather than desen- et al., 1984). It has been associated with ASD in dizy- sitized. Serotonin receptors are also enhanced in gotic twins from tocolytic delivery (Connors et al., numbers. These affects disrupt downstream adenyl 2005). The administration of the drug for 2 weeks or cyclase signaling, adversely affecting neuronal cell more had an increased concordance with twins (RR division and differentiation. In addition, terbutaline ¼ 2.0), which was increased to an RR of 4.0 for male activates microglia, leading to proinflammatory con- twins. In addition, a significant association (p < 0.006) ditions and gliosis in the developing brain (Cousin was found between the presence of 26G and 27E poly- and Seidler, 2001; Meyer et al., 2005; Slotkin et al., morphism of the beta-2-adrenergic receptors in these 2003; Zerrate et al., 2007). Following administration to rat pups on the second to fifth postnatal days, terbu- The adverse pathology and pharmacology effects taline caused neuronal injury shown by enzymes, caused by terbutaline have been investigated in the glial-fibrillar acidic protein, and induction of the neonatal rat brain at stages equivalent to specific K-68 Dalton neurofilament protein and reactive glio- times of human brain differentiation. Rodent studies sis with structural changes in cerebellum, hippocam- have shown that administration of terbutaline at pus, and somatosensory cerebral cortex. Such critical stages of neurodevelopment causes eight effects also appear to occur in humans along with neo- alterations. (1) Neuronal injury and reactive gliosis natal toxicity (Connors et al., 2005; Thorkelsson and that affects the cerebellum, hippocampus, and somatosensory cortex (Rhodes et al., 2004, Sospedra This new hypothesis suggests that epidemiological and Martin 2005); (2) Robust activation of microglia studies that incorporate objective testing of brain and results in abnormal behavior (Rhodes et al., 2004); lung function and amniocentesis for chemical analysis (3) Sensitization of beta-2-adrenoreceptors to beta- of proteins and enzymes could yield insight into cau- agonists (Slotkin et al, 2002; Rhodes et al., 2004; Toxicology and Industrial Health 25(9-10) Carey B (2007) Study puts rate of Autism at 1 in 150 U.S.
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