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

Immunologic abnormalities in humans exposed to chlorpyrifos: preliminary observations.

Twelve individuals who were exposed to chlorpyrifos were studied 1-4.5 y following exposure to determine changes in the peripheral immune system. The subjects were found to have a high rate of atopy and antibiotic sensitivities, elevated CD26 cells (p < .01), and a higher rate of autoimmunity, compared with two control groups. Autoantibodies were directed toward smooth muscle, parietal cell, brush border, thyroid gland, myelin, and ANA. Chlorpyrifos exposure was implicated in the immunologic abnormalities reported. The immunologic changes were similar to those reported for other pesticides.

Immunologic biomarkers associated with an acute exposure to exothermic byproducts of a ureaformaldehyde spill.

A community was exposed for several days to formaldehyde (HCHO), hexamethylenetetramine, trimethylamine, and paraformaldehyde emitted from an overheated tanker car containing ureaformaldehyde resin. Residents experienced acute HCHO symptoms at the time of the accident. Many developed chronic, multiple organ health complaints. Three years following the accident, exposed subjects were compared to residents of a nearby unexposed community for the following immunological parameters: white blood cell count, total lymphocyte count, percent and total lymphocyte subsets (CD5, CD4, CD8, CD19, CD25, and CD26 cells), prevalence of autoantibodies, and antibodies to HCHO-human serum albumin (HCHO-HSA) conjugate. The data were adjusted for gender, age, history of smoking, mobile home residency, and use of wood stoves. There was a statistically significant difference for the following: elevated percent and absolute numbers of CD26 cells (p less than 0.0001); autoantibodies (p less than 0.004), and greater titers of isotypes IgG (p less than 0.0005) and IgM (p less than 0.005) to HCHO-HSA. It is concluded that the exposed subjects had an activated immune system in addition to the elevated autoantibodies. Also, isotypes to HCHO-HSA resulted from the exposure and no other sources, such as smoking, mobile home residency, and use of wood stoves.

Immune activation and autoantibodies in humans with long-term inhalation exposure to formaldehyde.

Four groups of patients with long-term inhalation exposure to formaldehyde (HCHO) were compared with controls who had short-term periodic exposure to HCHO. The following were determined for all groups: total white cell, lymphocyte, and T cell counts; T helper/suppressor ratios; total Ta1+, IL2+, and B cell counts; antibodies to formaldehyde-human serum albumin (HCHO-HSA) conjugate and autoantibodies. When compared with the controls, the patients had significantly higher antibody titers to HCHO-HSA. In addition, significant increases in Ta1+, IL2+, and B cells and autoantibodies were observed. Immune activation, autoantibodies, and anti-HCHO-HSA antibodies are associated with long-term formaldehyde inhalation.

Building-related illness and antibodies to albumin conjugates of formaldehyde, toluene diisocyanate, and trimellitic anhydride.

A case of building-related health complaints was investigated with respect to the relationship among frequency of symptoms, antibodies to albumin conjugates of formaldehyde (HCHO), toluene diisocyanate (TDI), and tirmellitic anhydride (TMA), and volatile organic chemicals (VOCs). The indoor air concentrations of VOCs, HCHO, TDI, and TMA did not exceed Fed-OSHA and ACGIH permissible standards. However, HCHO concentrations ranged between 0.05 and 0.08 ppm. The reported symptoms were multiple, involving the eyes, nose, sinuses, throat, lungs, skeletomuscular system, and central nervous system. Anti-HCHO, -TDI, and -TMA isotypes were found in 12 of 14 full-time employees and were nondetectable in one part-time employee. There was a positive, but not statistically significant, correlation (r values ranged between .24 and .55) between symptoms and the geometric mean titers to conjugates. The data suggest that a synergistic immunological response to airborne chemicals may be occurring in these subjects. In conclusion, immunological monitoring of affected individuals where chemicals are suspected may prove to be useful in future investigations of building-related illness.

Immunological evaluation of four arc welders exposed to fumes from ignited polyurethane (isocyanate) foam: antibodies and immune profiles.

Four arc welders having a flu-like illness with multiple health complaints following an exposure to high concentrations of isocyanate fumes from ignited polyurethane foam underwent immunological tests as follows: ELISA antibody assays, activated lymphocyte profiles, and lymphocyte blastogenesis. ELISA procedures revealed the presence of antibodies to hexamethylene diisocyanate (HDI) and formaldehyde (F) conjugated to human serum albumin (HDI-SA and F-SA). The results from the activated lymphocyte profiles showed deviations from the norm as follows: three welders had elevated helper/suppressor (H/S) ratios; all four had elevated percentages of Tal positive cells; two had decreases in B cells; and one had low total white cell and lymphocyte counts. In contrast, the percentage and absolute numbers of ILS receptor cells were normal in the four subjects. T cell blastogenesis to PHA, Con A and PWM resulted in the following: T-cells from one subject responded normally; in another, a high response (212% of controls) to PHA occurred with normal mitogenesis to Con A and PWM. In the remaining two welders, the T cells responded abnormally low (50 to 75% of controls) to the three mitogens. In conclusion, the existence of IgG antibodies to HDI-SA and F-SA, the altered activated immune profiles, the elevated Tal cells, and the abnormal blastogenesis are interpreted as being linked with the episode of HDI and F exposure and the subsequent flu-like illness of the four welders.

Antibodies and immune profiles of individuals occupationally exposed to formaldehyde: six case reports.

Six patients with multiple subjective health complaints, which have been correlated with chronic exposure to formaldehyde during the course of their education and occupations, were tested for the existence of antibodies (IgE, IgM, and IgG) to formaldehyde (F) conjugated to human serum albumin (F-HSA). In addition, the percentage and absolute numbers of peripheral lymphocyte subpopulations as determined by surface markers were investigated. Antibody titers to F-HSA were present as follows: IgE (2 patients), IgM (3 of 4 tested patients), and IgG (5 patients). Analysis of lymphocyte subpopulations showed T-helper/suppressor (H/S) ratios ranging from 0.8 to 3.3. All 6 patients had elevated Tal cells (antigen memory cells), whereas interleuken 2 receptor positive cells were within expected values. Following formaldehyde exposure, 5 of the patients complained of an initial flulike illness from which they have not completely recovered. The sixth individual had a history of recurrent respiratory infections and surgical removal of hyperplastic ethmoid sinus tissue. The common occurrence of anti-F-HSA antibodies, flulike illness, and Tal cells are interpreted as suggestive of a chronic antigenic stimulation of the immune system in these 6 patients. Further immunological work-up of additional subjects and immune parameters with similar history of formaldehyde exposure and subjective health complaints is warranted.

Evidence for formaldehyde antibodies and altered cellular immunity in subjects exposed to formaldehyde in mobile homes.

Eight symptomatic individuals chronically exposed to indoor formaldehyde (HCHO) at low concentrations (0.07-0.55 ppm) were compared to 8 nonexposed subjects with respect to: (1) presence of IgG and IgE antibodies to HCHO conjugated to human serum albumin (F-HSA); (2) the percentage of venous blood T and B cells by E and EAC-rosetting; and (3) the ability of T and B cells to undergo mitogen (PHA, PWM) stimulated blastogenesis as measured by the incorporation of tritiated thymidine. Anti-F-HSA IgG, but no IgE, antibodies were detected in the sera of the 8 exposed subjects; none were found in 7 of the unexposed controls. T lymphocytes were decreased in the exposed (48 +/- 11.5%) compared to the control (65.9 +/- 4.97%) subjects (p greater than .001 less than .01). B cells were 12.6 +/- 1.6% (HCHO group) and 14.75 +/- 2.1% (controls) (p greater than .02 less than .05). The incorporation of labeled thymidine by T cells (PHA) was decreased: 17,882 +/- 2,293 cpm (HCHO group) and 28,576 +/- 3,807 cpm (p greater than .001 less than .01). T and B cell blastogenesis (PWM) was 9,698 +/- 1,441 cpm (HCHO group) and 11,279 +/- 1,711 (controls) (p greater than .05 less than .1). Exposure to HCHO appears to stimulate IgG antibodies to F-HSA and decrease the proportion of peripheral T cells.