Kaye H. Kilburn

Prevalence of symptoms of systemic lupus erythematosus (SLE) and of fluorescent antinuclear antibodies associated with chronic exposure to trichloroethylene and other chemicals in well water

Criteria for the recognition of systemic lupus erythematosus (SLE) were applied to 362 subjects exposed to trichloroethylene, trichloroethane, inorganic chromium, and other chemicals in water obtained from wells in an industrially contaminated aquifer in Tucson, Arizona. Their antinuclear autoantibodies were measured by fluorescence (FANA) in serum. Ten patients with clinical SLE and/or other collagen-vascular diseases were considered separately. Results were compared to an Arizona control group, to published series, and to laboratory controls. Frequencies of each of 10 ARA symptoms were higher in exposed subjects than in any comparison group except those with clinical SLE. The number of subjects than in any comparison group except those with clinical SLE. The number of subjects with 4 or more symptoms was 2.3 times higher compared to referent women and men. FANA titers greater than 1:80 was approximately 2.3 times higher in women but equally frequent in men as in laboratory controls. ARA score and FANA rank were correlated with a coefficient (cc) of .1251, r2 = .0205 (p less than 0.036) in women and this correlation was almost statistically significant in men cc = .1282, r2 = .0253 (p less than 0.059). In control men and women neither correlation was significant. Long-term low-dose exposure to TCE and other chemicals in contaminated well water significantly increased symptoms of lupus erythematosus as perceived by the ARA score and the increased FANA titers.

Neurobehavioral and respiratory symptoms of formaldehyde and xylene exposure in histology technicians

Disturbances of memory, mood, equilibrium, and sleep that occurred simultaneously with headache and indigestion, were experienced more frequently among women working in histology who had daily exposure to formaldehyde, xylene, and toluene than in unexposed female clerical workers working in the same hospitals. Neurobehavioral symptoms were accompanied by irritation of eyes, upper airways, and trachea. Formaldehyde exposure correlated better with neurobehavioral symptoms and with respiratory and mucous membrane symptoms than did exposure to xylene/toluene or to other agents.

Embryo Toxicity and Teratogenicity of Formaldehyde

Abstract 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 AC, 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 Hartley 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 effects on ovarian elements (e.g., thecal cells and ova [nuclear-deoxyribonucleic acid and mitochondrial deoxyribonucleic acid]), as well as on zygotes and embryos before implantation. Mitochondrial deoxyribonucleic acid mutations and deletions occur in human oocytes and embryos (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 is likely that xenobiotics directly affect n-deoxyribonucleic acid and/or mitochondrial deoxyribonucleic acid in either the ovum or the zygote/embryo or both (Thrasher JD. Arch Environ Health 2000, pp 292–94 [reference 18 herein]), and they could account for the increasing appearance of a variety of mitochondrial diseases, including autism (Lomard L. Med Hypotheses 1998, pp 497–99; Wallace EC. Proc Natl Acad Sci 1994, pp 8730–46; and Giles RE, et al. Proc Natl Acad Sci 1980, pp 6715–19 [references 19–21, respectively, herein]). Two cases of human birth defects were reported in formaldehyde-contaminated homes (Woodbury MA, et al. Formaldehyde Toxicity 1983; pp 203–11 [reference 22 herein]). One case was anencephalic at 2.76 ppm, and the other defect at 0.54 ppm was not characterized. Further observations on human birth defects are recommended.

Interaction of asbestos, age, and cigarette smoking in producing radiographic evidence of diffuse pulmonary fibrosis

The study of 3,472 chest x-rays from four populations with different levels of exposure to asbestos and with different cigarette smoking histories shows that smoking in the general population does not produce pulmonary fibrosis recognizable on chest radiography. In the general population of Michigan, the prevalence of a radiographic pattern of fibrosis was 0.5 percent in men and 0.0 percent in women. In a Long Beach, California census tract population, the prevalences were 3.7 percent for men and 0.6 percent for women. Similarly, cigarette smoking does not enhance fibrosis when the exposure to asbestos has been as light as that in households of shipyard workers. Asbestosis was recognized in 6.6 percent of 137 shipyard workers wives who have never smoked and 7.6 percent of 132 who had ever smoked. Cigarette smoking and asbestos appear to be synergistic in those occupationally exposed to asbestos (as insulators), since 7.2 percent of 97 nonsmokers and 20.5 percent of 316 ever-smokers showed fibrosis. This apparent synergy was also found in shipyard workers up to age 70 with 31 percent of nonsmokers and 43.3 percent of ever-smokers having fibrosis. There were increases of approximately 10 percent in the prevalence of fibrosis in cigarette smokers and nonsmokers for each decade after age 40.

Pulmonary and Neurobehavioral Effects of Formaldehyde Exposure

Two groups of male workers who were exposed to formaldehyde, the first group in phenol-formaldehyde-plastic foam matrix embedding of fiberglass (batt making), and the second in the fixation of tissues for histology, were studied for work-related neuro-behavioral, respiratory, and dermatological symptoms; and for pulmonary functional impairment. Forty-five male fiberglass batt makers who were studied across the initial work-shift after a holiday had average frequencies of combined neurobehavioral, respiratory, and dermatological symptoms of 17.3 for the hot areas and 14.7 for the cold areas of the process. Their symptom counts were significantly greater than those for 18 male histology technicians who averaged 7.3, and for 26 unexposed male hospital workers who averaged 4.8. During their first workshift after holidays, 58% of the batt makers had a decrease in one or more tests of pulmonary function. Nine nonsmokers had decreases more frequently than did 35 smokers; forced expiratory volume in one second FEV1.0 decreased in 16%, diffusing capacity for carbon monoxide (sb) decreased in 30%, forced expiratory flow 25-75 decreased in 16%, and forced expiratory flow) 75-85 decreased in 36%. Thirty-five percent of all 44 men had drops in FEV1.0, forced vital capacity, or in diffusing capacity (sb).

Neurobehavioral effects of formaldehyde and solvents on histology technicians : repeated testing across time

Neurobehavioral functions were studied by periodic testing of 318 histology technicians and by a single session testing 494 of such technicians from 1982 through 1986. Tests included immediate recall of stories, of drawings, and of number series from the Wechsler Memory Scale, block designs from the Wechsler Adult Intelligence Scale (WAIS), slotted pegboard, trail making A and B, embedded figures, number writing on the fingers, visual simple and two-choice reaction times, balance (speed of body sway), and the profile of mood state (POMS) score. Mean test scores of four initial first test groups were not different from 1982 to 1986. Immediate recall of stories and drawings improved on the first retest as did the block design score. Other test scores showed insignificant variation over the 4 years, including memory for numbers forward and backward, trails A and B, number writing on fingers, radius of body sway, and choice reaction time. Only placing of pegs in the pegboard took longer. POMS score was lower in the second year in naive subjects and decreased from 39 to 13 in those retested. Variations in results of neurobehavioral tests given at intervals across 4 years were small. No cumulative effects of occupational exposures or of aging were found. However, small decreases may have been offset by increases due to test familiarity or learning.

Effects of diesel exhaust on neurobehavioral and pulmonary functions.

Abstract 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.

Indoor Air Effects after Building Renovation and in Manufactured Homes

PROBLEMnThe 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.nnnMETHODSnTen 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.nnnRESULTSnExposures 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.nnnCONCLUSIONSnAdverse 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.

Case report: profound neurobehavioral deficits in an oil field worker overcome by hydrogen sulfide

A 24-year-old oil well tester was rendered semiconscious by hydrogen sulfide (H2S). He received oxygen and was hospitalized but released in 30 minutes. The next day, nausea, vomiting, diarrhea, and incontinence of urine and stool led to rehospitalization. These problems and leg shaking, dizziness, sweating, trouble sleeping, and nightmares prevented his return to work. A physical examination, chest x-ray, and pulmonary function tests were normal 39 months after the episode but vibration sense was diminished. Two choice visual reaction times were delayed. Balance was highly abnormal (5 to 6 cm/sec) with eyes closed. Blink reflex latency was slow (R-1 17.5 msec versus normal 14.3 msec). Numbers written on finger tips were not recognized. Verbal and visual recall were impaired but overlearned memory was intact. Cognitive functions measured by Culture Fair, block design, and digit symbol were impaired. Perceptual motor was slow. Scores for confusion, tension-anxiety, depression, and fatigue were elevated and vigor was reduced. Forty-nine months after exposure his reaction time, sway speed, and color vision had not improved. His recall and his cognitive, constructional, and psychomotor speeds had improved but remained abnormal. These deficits are most likely due to H2S. Similar testing of other survivors is recommended.

Is Neurotoxicity Associated with Environmental Trichloroethylene (TCE)

Abstract Individuals who lived near 2 electronic manufacturing plants were exposed to odorous chlorinated solvents by inhalation (directly) and by outgassing from well water. An exposure zone was defined by concentrations of trichloroethylene, 1,1,1-trichloroethane, tetrachloroethylene, and vinyl chloride in groundwater. The author adopted trichloroethylene as a “shorthand” for the exposure designation. Residents complained of impaired recall and concentration, and of dizziness; therefore, the focus of this investigation was brain functions. Neurobehavioral functions, Profile of Mood States, frequencies of 35 symptoms, and questionnaire responses provided by 236 residents from exposure zones were compared with responses provided by 161 unexposed regional referents and by 67 Phoenix residents who lived outside the exposure zone areas. Pulmonary functions were measured with spirometry. Residents of the exposure zones were compared with regional referents, and the former had significantly (p < .05) delayed simple and choice reaction times, impaired balance, delayed blink reflex latency R-1, and abnormal color discrimination. In addition, these individuals had impaired (1) cognitive functions, (2) attention and perceptual motor speed, and (3) recall. Individuals who lived in exposure zones had airway obstructions. Adverse mood state scores and frequencies of 33 of 35 symptoms were elevated. In conclusion, individuals who lived in the exposure zones had neurobehavioral impairments, reduced pulmonary functions, elevated Profile of Mood State scores, and excessive symptom frequencies.