Embryo toxicity and teratogenicity of formaldehyde.

C-14 formaldehyde crosses the placenta and enters fetal tissues. The incorporated radioactivity is higher in fetal organs (i.e., brain and liver) than in maternal tissues. The incorporation mechanism has not been studied fully, but formaldehyde enters the single-carbon cycle and is incorporated as a methyl group into nucleic acids and proteins. Also, formaldehyde reacts chemically with organic compounds (e.g., deoxyribonucleic acid, nucleosides, nucleotides, proteins, amino acids) by addition and condensation reactions, thus forming adducts and deoxyribonucleic acid-protein crosslinks. The following questions must be addressed: What adducts (e.g., N-methyl amino acids) are formed in the blood following formaldehyde inhalation? What role do N-methyl-amino adducts play in alkylation of nuclear and mitochondrial deoxyribonucleic acid, as well as mitochondrial peroxidation? The fact that the free formaldehyde pool in blood is not affected following exposure to the chemical does not mean that formaldehyde is not involved in altering cell and deoxyribonucleic acid characteristics beyond the nasal cavity. The teratogenic effect of formaldehyde in the English literature has been sought, beginning on the 6th day of pregnancy (i.e., rodents) (Saillenfait AM, et al. Food Chem Toxicol 1989, pp 545-48; Martin WJ. Reprod Toxicol 1990, pp 237-39; Ulsamer AG, et al. Hazard Assessment of Chemicals; Academic Press, 1984, pp 337-400; and U.S. Department of Health and Human Services. Toxicological Profile of Formaldehyde; ATSDR, 1999 [references 1-4, respectively, herein]). The exposure regimen is critical and may account for the differences in outcomes. Pregnant rats were exposed (a) prior to mating, (b) during mating, (c) or during the entire gestation period. These regimens (a) increased embryo mortality; (b) increased fetal anomalies (i.e., cryptochordism and aberrant ossification centers); (c) decreased concentrations of ascorbic acid; and (d) caused abnormalities in enzymes of mitochondria, lysosomes, and the endoplasmic reticulum. The alterations in enzymatic activity persisted 4 mo following birth. In addition, formaldehyde caused metabolic acidosis, which was augmented by iron deficiency. Furthermore, newborns exposed to formaldehyde in utero had abnormal performances in open-field tests. Disparities in teratogenic effects of toxic chemicals are not unusual. For example, chlorpyrifos has not produced teratogenic effects in rats when mothers are exposed on days 6-15 (Katakura Y, et al. Br J Ind Med 1993, pp 176-82 [reference 5 herein]) of gestation (Breslin WJ, et al. Fund Appl Toxicol 1996, pp 119-30; and Hanley TR, et al. Toxicol Sci 2000, pp 100-08 [references 6 and 7, respectively, herein]). However, either changing the endpoints for measurement or exposing neonates during periods of neurogenesis (days 1-14 following birth) and during subsequent developmental periods produced adverse effects. These effects included neuroapoptosis, decreased deoxyribonucleic acid and ribonucleic acid synthesis, abnormalities in adenylyl cyclase cascade, and neurobehavioral effects (Johnson DE, et al. Brain Res Bull 1998, pp 143-47; Lassiter TL, et al. Toxicol Sci 1999, pp 92-100; Chakraborti TK, et al. Pharmacol Biochem Behav 1993, pp 219-24; Whitney KD, et al. Toxicol Appl Pharm 1995, pp 53-62; Chanda SM, et al. Pharmacol Biochem Behav 1996, pp 771-76; Dam K, et al. Devel Brain Res 1998, pp 39-45; Campbell CG, et al. Brain Res Bull 1997, pp 179-89; and Xong X, et al. Toxicol Appl Pharm 1997, pp 158-74 [references 8-15, respectively, herein]). Furthermore, the terata caused by thalidomide is a graphic human example in which the animal model and timing of exposure were key factors (Parman T, et al. Natl Med 1999, pp 582-85; and Brenner CA, et al. Mol Human Repro 1998, pp 887-92 [references 16 and 17, respectively, herein]). Thus, it appears that more sensitive endpoints (e.g., enzyme activity, generation of reactive oxygen species, timing of exposure) for the measurement of toxic effects of environmental agents on embryos, fetuses, and neonates are more coherent than are gross terata observations. The perinatal period from the end of organogenesis to the end of the neonatal period in humans approximates the 28th day of gestation to 4 wk postpartum. Therefore, researchers must investigate similar stages of development (e.g., neurogenesis occurs in the 3rd trimester in humans and neonatal days occur during days 1-14 in rats and mice, whereas guinea pigs behave more like humans). Finally, screening for teratogenic events should also include exposure of females before mating or shortly following mating. Such a regimen is fruitful inasmuch as environmental agents cause adverse effec

Function testing for chemical brain damage: a review.

Testing of neurobehavioral functions for evaluation of the effects of chemicals on the human brain from community (i.e., environmental) exposures is logical and may be a preferred initial step. Sensitivity is improved (1) by adjusting individual tests for influential factors, found by regression modeling and by retaining significant coefficients; and (2) by the calculation of predicted values for each test for each subject. This two-part approach allows for adjustments in age, sex, educational level, and other factors before comparisons are made. Visual fields, color discrimination, reaction time, balance, and digit symbol are the most sensitive tests, followed by 6 sensitive psychological tests and less-discriminating physiological measurements. Hydrogen sulfide, polychlorinated biphenyls, and arsenic are the most toxic chemicals, followed by chlorine, chlorpyrifos, formaldehyde, nickel carbonyl, and ammonia. The least toxic chemicals, which are hydrochloric acid and chlorine, were determined 7 wk following a community spill. The least toxic chemical among those identified herein is methyl ter butyl ether.

Indoor air effects after building renovation and in manufactured homes.

PROBLEM: The objective was to measure and compare the neurobehavioral and respiratory effects of exposures to indoor air in people living in manufactured homes and occupying buildings during renovation and compare them with effects on subjects exposed to formaldehyde at work. METHODS: Ten people living in manufactured homes and 10 people exposed to chemicals during renovation of their offices or homes had measurements made of balance, visual fields, reaction time, hearing, grip strength, and vibration sense. Psychological measurements included cognition, recall, perceptual motor speed, long-term memory, and mood states. RESULTS: Exposures to indoor air were associated with abnormal simple and choice reaction time, abnormal balance with the eyes open and with the eyes closed, abnormalities of color confusion index, scotoma in visual fields, reduced verbal recall, digit symbol score, and elevated abnormal moods. The effects on the two groups of 10 were similar and resembled those from formaldehyde exposure but with less cognitive impairment. CONCLUSIONS: Adverse effects from indoor air in manufactured homes and during renovations were less severe but similar to those from occupational formaldehyde exposures. This suggests that formaldehyde has a major role in health problems from indoor air.

Visual and neurobehavioral impairment associated with polychlorinated biphenyls.

To determine whether residents exposed to PCBs and thermolysis products had impaired neurobehavioral functions, the performance of 98 exposed adults was compared with 58 unexposed regional referents (all volunteers). Visual field performance, color confusion index, balance as sway speed, blink reflex latency R-1, hearing, grip strength, simple and choice visual reaction times problem solving for Culture Fair and digit symbol, recall memory, peg placement, trail making A and B for attention and dexterity and long-term memory were tested. A profile of mood states (POMS) and questionnaires for chemical exposures, medical histories and the frequency of 35 symptoms were completed. Only statistically significant differences are described. Exposed subjects had slower simple and choice reaction times and faster sway speeds with eyes closed and open. Color discrimination and visual performance scores were lower and visual fields were often constricted. Scores on Culture Fair, digit symbol, vocabulary and verbal recall were lower. Placement of pegs in a slotted pegboard was slower and trail making A and B took longer. Even embedded memory test scores including vocabulary were lower. POMS scores were elevated. There were no competing chemical exposures, confounding factors or other explanations for the findings. Long residential exposure to PCBs was associated with visual defects and impaired neurophysiologic and neuropsychologic functions.

Prevalence and features of advanced asbestosis (ILO profusion scores above 2/2). International Labour Office.

In this study, the author addressed the following question: Do workers with advanced asbestosis have a restrictive pulmonary physiology, and, alternately, do those who have restrictive physiological tests have advanced asbestosis? One group was identified by obvious radiographic measurements, and the other group was defined via physiologic measurements. Total lung capacity, vital capacity, and flows were measured in 12,856 men exposed to asbestos, of whom 3,445 had radiographic signs of asbestosis, as defined by the International Labour Office criteria. Radiographically advanced asbestosis-International Labour Office criteria profusion greater than 2/2 was present in 85 (2.5%) of men. An additional 52 men had physiologically restrictive disease. The author, who compared pulmonary flows and volumes of these two groups, used mean percentage predicted, adjusted for height, age, and duration of cigarette smoking. Men with radiographically advanced asbestosis had normal total lung capacity (i.e., 105.5% predicted), reduced forced vital capacities (i.e., 82.7% predicted), air trapping (i.e., residual volume/total lung capacity increased to 54.4%), and reduced flows (i.e., forced expiratory flow [FEF25-75] = 60.6% predicted, forced expiratory volume in 1 s = 78.0% predicted, and forced expiratory volume in 1 s/forced vital capacity = 65.5%). In contrast, men selected from the same exposed population for restrictive disease (i.e., reduced total lung capacity [72.6% predicted] and forced vital capacity [61.5% predicted]) also had airflow obstruction (i.e., forced expiratory volume in 1 s/forced vital capacity of 74.5% predicted) and air trapping (i.e., residual volume/total lung capacity of 46.7%). Only half of these men had asbestosis--and it was of minimal severity. In summary, advanced asbestosis was characterized by airway obstruction and air trapping, both of which reduced vital capacity but not total lung capacity; therefore, it was not a restrictive disease. In contrast, restrictive disease was rare and was associated with minimal asbestosis.

Effects of diesel exhaust on neurobehavioral and pulmonary functions.

Ten railroad workers and 6 electricians referred for shortness of breath also had slowness of response, memory loss, and disordered sleep, all of which suggested neurobehavioral impairment. The hypothesis was that diesel exhaust causes central nervous system impairment. Six electricians worked within enclosed concrete walls and roofs that trapped diesel exhaust from trucks. Seven railroad mechanics had tuned diesel engines indoors for 15-50 y, and 3 crewmen rode in locomotives. Neurobehavioral and visual functions were measured with a 26-test battery. Compared with unexposed men, the 16 in this study had significantly impaired reaction time, balance, blink reflex latency R-1, Culture Fair, peg placement, trail making, and verbal recall. Thirteen men had abnormal visual fields, and 11 had abnormal color confusion indices. Nine men had airways obstruction. The author could not attribute abnormalities to confounding factors or bias. Severe neurobehavioral impairment was associated with exposure to confined diesel exhaust. In additional studies of diesel-exposed workers, especially drivers of locomotives and trucks, investigators should use sensitive neurobehavioral methods.

Chlorine-induced damage documented by neurophysiological, neuropsychological, and pulmonary testing.

Chlorine causes acute pulmonary edema and damages airways, thus producing obliterative bronchiolitis. In the case series in this study, its adverse effects were extended to visual and central nervous system impairment. Twenty-two patients exposed briefly to undiluted chlorine at home or work were evaluated with a battery of neurobehavioral and visual tests. Their test scores, expressed as percentage predicted, were compared with those of unexposed subjects. Chlorine-exposed subjects had impaired balance (with eyes open and eyes closed), delayed simple and choice reaction times, impaired color discrimination, impaired visual field performance, decreased hearing, and decreased grip strength. Blink reflex latency was delayed on the right. Cognitive performance (i.e., digit symbol and vocabulary), peg placement, trail making A and B, and verbal recall were significantly below predicted levels. Well-learned memory functions were not impaired. Adverse mood states scores were elevated as were the frequencies of 28 of 35 common symptoms. Forced vital capacities were reduced. The duration of chlorine exposures was from a breath or two to several hours, and exposures were associated with impaired neurophysiologic and neuropsychologic functions. Impairments appeared insidiously, were noted 1 to 48 mo after exposure, and persisted. Such functional losses must be prevented. Additional chlorine-exposed patients should be evaluated for neurological and pulmonary damage.

Neurotoxicity from airborne chemicals around a superfund site.

A pilot investigation had shown that 88 people living within 2.4 km of a waste chemical disposal and oil-reprocessing facility which operated from 1966 to 1983 had reduced neurobehavioral performance compared to 66 regional referents. A geographic model of dispersal predicted less effect with greater distance from the distilling. To explore this gradient and the boundaries of the adverse effects, we tested 408 residents in random proportional samples of concentric zones from the center out to 4.8 km that were divided by compass octants. Reaction times, balance, blink reflex latency, color discrimination, Culture Fair, pegboard, and Trail Making A and B were measured. Patients completed a Profile of Mood States, frequency of 33 symptoms, and medical, occupational, and exposure histories. Distance and direction from the site and duration of residence were examined for effect on each test score by stepwise linear regression. Exposed subjects' had diminished reaction time, balance, color score, and scores for Culture Fair, pegboard, and Trail Making A and B compared to referents. Functional impairment was not correlated with distance or direction from the site but subjects with short durations of residence had better function on one test. Combinations of these factors were not predictive.

Neurobehavioral and respiratory findings in jet engine repair workers: A comparison of exposed and unexposed volunteers.

Workers repairing jet engines had respiratory, rheumatic, and neurobehavioral symptoms. They had welded and ground stainless steel parts using hard metal tools and cleaned metal with chlorinated and fluorinated organic solvents. We compared 154 workers and 112 unexposed subjects, all volunteers of similar ages and with similar educational levels, for abnormalities on chest radiographs, spirometric measurements, and questionnaires. Also appraised were performance of reaction time, balance, blink reflex latency, color discrimination, Culture Fair, vocabulary, slotted pegboard, trail making A and B, profile of mood states (POMS), and frequencies of 35 symptoms. Compared to unexposed subjects, workers had significantly more respiratory symptoms but no differences in pulmonary function. They had significantly prolonged simple and choice reaction time (P<0.0001), and abnormal balance with eyes open and eyes closed (P<0. 0001), and abnormal color discrimination. Blink reflex latency was abnormal in both exposed workers and in local unexposed compared to other reference groups. Focus of the inquiry on lung disease helped ensure that for neurobehavioral tests confounding factors were minimal and known biases were small. We tentatively attribute the neurobehavioral impairments and increased symptom frequencies to chlorinated solvent exposure. Excessive respiratory symptoms are attributed to welding stainless steel combined with cigarette smoking. Specifically, manganese exposure may have affected the respiratory and the central nervous systems.

Neurobehavioral impairment and symptoms associated with aluminum remelting.

The author's objective was to assess whether aluminum reclamation (recycling) exposure in a plant in the southeastern United States was associated with neurobehavioral and pulmonary impairment and symptoms. The author made cross-sectional comparisons of 41 workers to 32 local and 66 regional referents to assess whether aluminum recycling was associated with neurobehavioral and pulmonary impairment and symptoms. Methods included neurophysiological, psychological, and pulmonary-function tests; a Profile of Mood States (POMS); and questionnaires. The exposed subjects had slower simple and choice reaction times than referents (i.e., 77 milliseconds [ms] versus 137 ms, respectively [p < .0001]); balance in the exposed subjects, measured as sway speed (with eyes closed), was .32 cm/s faster than for referents (p < .005); and color discrimination was less acute in exposed subjects (p < .0001). In the exposed versus referent subjects, Culture Fair scores were lower by a factor of 8.3 (p < .0001), Trail Making A was 10 s longer (p < .001), Trail Making B was 50 s longer (p < .0001), peg placement required an additional 9 s (p < .008), and POMS scores were fourfold higher (p < .0001). These described differences were not explained by age, bias, or confounding factors. Workers had more neurobehavioral, rheumatic, and respiratory symptoms than did referents. The author attributed the differences between the two groups to chemical exposures from aluminum remelting, including aluminum, manganese, vinyl chloride monomer, and other chemicals. Workplace air could not be sampled, but because a problem was identified, levels of these, as well as other chemicals, should be measured in future studies.

Population-based prediction equations for neurobehavioral tests.

Quantitative assessment of neurobehavioral function appraises brain injury from inhaled chemicals. Contemporary predicted values for tests useful in epidemiological studies have been developed with step-wise linear regression. In instances in which age and education do not match those of control groups, these equations assist in the interpretation of results of examinations of individual subjects and pilot studies. In this study, investigators considered brain function tests to be analogous in concept to pulmonary function tests. The authors used the tests to assess 293 adults in three unexposed groups from different areas of the United States. The subjects, who were contacted at random from voter registration rolls, were compensated for their time. The tests included balance, reaction time, strength, hearing, visual performance and cognitive recall, and perceptual motor and memory functions. Regression equations modeled the performance of each test and the influences of demographic factors. The investigators retained all influential factors in the equations. Age was a significant predictor for most tests. Education attainment was not a factor in any of the physiological measures, but it was a determinant in many psychological tests. Prediction equations assist investigators in the quantitative testing of chemically exposed individuals and other brain-injured individuals. The investigators verified the equations against other groups, including additional unexposed populations.

A field method for blink reflex latency R-1 (BRL R-1) and prediction equations for adults and children.

PURPOSE: To develop a field worthy apparatus for blink reflex latency R-1 (BRL R-1), to compare mechanical and electrical stimulation, to define a standardized measurement of BRL R-1, to test a field worthy procedure and to produce population-based prediction equations. METHODS: A special low voltage electromyographic (EMG) recording system was constructed which is uninfluenced by electrical and magnetic field. The supraorbital notches were stimulated mechanically using a small hammer and electrically using a stimulus of 2.0 ms duration and 2-5 mA 13. A computer program was developed which substracts the baseline for all data points and sums R-1 for 10 tests by identifying the noise floor or baseline of the EMG recording and the noise envelope. The beginning of R-1 and R-2 is defined as 2 times the noise amplitude of this envelope. BRL R-1 was compared after tap and after electrical stimulation in 16 subjects. Prediction equations were developed from data of 240 adults and 163 children unexposed to chemicals. RESULTS: Mechanically and electrically elicited mean BRL R-1 in 16 subjects was identical at 12.6 ms on the right and 12.7 ms vs 12.5 on the left. In adults, BRL R-1 depended on age. In children BRL R-1 was age, weight and height dependent. CONCLUSION: BRL R-1 elicited by supraorbital tap is field worthy, computer defined and identical to electrical BRL.

Exposure to reduced sulfur gases impairs neurobehavioral function.

BACKGROUND: In the 19th century, deaths from acute exposure to hydrogen sulfide (H2S) portended permanent brain injury from nonlethal doses. The neurobehavioral effects of H2S exposures lasting from moments to years were compared in 16 subjects, 2 years to 22 years afterward. METHODS: Neurophysiologic and psychologic tests were used to appraise mood status and frequencies of 35 symptoms. Functions and frequencies, described as percent predicted adjusted for age, sex, educational achievement, and other factors, were compared with those in an unexposed population. RESULTS: Frequencies were elevated for 31 of 33 symptoms. Balance was impaired (246% predicted with eyes closed, 159% predicted with eyes open), and simple and choice reaction times were prolonged (151% and 130% predicted, respectively). Visual fields performance was decreased to 72% predicted (right) and 55% predicted (left), color discrimination was abnormal, and hearing was decreased. Psychologic domains showed cognitive disability, reduced perceptual motor speed, impaired verbal recall and remote memory, and abnormal mood status. CONCLUSIONS: Exposure to H2S must be avoided.

Chlordane as a neurotoxin in humans.

To assay and profile chronic neurobehavioral impairment associated with chlordane exposure in symptomatic patients, consecutive evaluations of nine patients were done with sensitive neurophysiologic and neuropsychologic tests for neurobehavioral function. Their visual fields, balance, reaction time, blink, color discrimination, grip strength, cognitive function, recall, memory, and perceptual motor speed were tested, and mood states and frequencies of 35 symptoms were appraised. Prevalences of abnormality were compared test-by-test to predict values with confidence intervals, and mean values for the group were compared with reference values. Testing showed abnormal balance with eyes closed in 7, abnormal color discrimination in 6, verbal recall deficit in 5, and prolonged blink reflex latency, prolonged choice reaction time, and decreased Culture Fair scores in 4 each. Profile of Mood States score was elevated in 5. These observations suggest that chlordane causes protracted neurotoxicity.

Prediction equations for simple and visual two-choice reactions times in environmental neurotoxicology.

To provide preliminary prediction equations for simple visual and two-choice visual reactions times, timed from the appearance of the letter A or S on a computer screen to cancellation, we modeled 264 randomly selected subjects from voter registration rolls in Arizona and Louisiana. These predicted values, validated by comparison to observed values and coefficients, were compared with those from a second population in California. We tested ability to detect abnormality by measuring a trichloroethylene-exposed population aged 17-70 y. The natural logarithm of simple visual reaction time was independent of age and other factors. The natural logarithm of two-choice visual reaction time was increased by age. These equations predict performance of groups that are studied with respect to neurobehavioral effects of chemicals, and the equations distinguish exposure and nonexposure for the range of adult ages. To define abnormality of individual subjects, we suggest use of the predicted value, plus 1.5 standard deviations; in this study, 8% of the model group was selected as abnormal.

Effects of a hydrochloric acid spill on neurobehavioral and pulmonary function.

A container truck leaked 800 L (200 gallons) of hydrochloric acid (HCl) near a mobile home park in Louisiana in August 1993. The investigating officer and residents became acutely ill with burning and tearing eyes, burning throats, headache, chest pain, shortness of breath, and flu-like complaints. Twenty months later, 45 exposed adult subjects and 56 age-matched referents underwent neurobehavioral testing, including balance, reaction time, blink-reflex latency, and spirometry. They also completed health questionnaires and a profile of mood states. The exposed subjects differed significantly from referents by t test and by covariance analysis for balance, simple and two-choice visual reaction time, digit symbol, and for placing pegs in a pegboard. Proximity to the HCl spill increased sway speeds and impaired pulmonary midflow rates. Chronic neurobehavioral dysfunction and airways obstruction were found after environmental HCl exposure.