Sensory irritation to mixtures of formaldehyde,acrolein, and acetaldehyde in rats

 Sensory irritation of formaldehyde (FRM), acrolein (ACR) and acetaldehyde (ACE) as measured by the decrease in breathing frequency (DBF) was studied in male Wistar rats using nose-only exposure. Groups of four rats were exposed to each of the single compounds separately or to mixtures of FRM, ACR and/or ACE. Exposure concentrations of the mixtures were chosen in such a way that summation of the effects of each chemical would be expected not to exceed 80% reduction of the breathing frequency. FRM, ACR and ACE appeared to act as sensory irritants as defined by Alarie (1966, 1973). With FRM and ACR desensitization occurred, whereas with ACE the breathing frequency gradually decreased with increasing exposure time (up to 30 min). For mixtures, the observed DBF was more pronounced than the DBF for each compound separately, but was less than the sum of the DBFs for the single compounds. A model for three compounds competing for the same receptor was applied to predict the DBF of mixtures of FRM, ACE and ACR. The results also showed that with mixtures no desensitization occurred; in fact, the breathing frequency further decreased in the last 15 min of exposure. These observations were similar to those found for ACE alone, and might have been caused by effects on the upper respiratory tract. The results of the present study allow the conclusion that sensory irritation in rats exposed to mixtures of irritant aldehydes is more pronounced than that caused by each of the aldehydes separately, and that the DBF as a result of exposure to a mixture could well be predicted using a model for competitive agonism, thus providing evidence that the combined effect of these aldehydes is basically a result of competition for a common receptor (trigeminal nerve). Received: 24 April 1995/Accepted: 26 September 1995     

Eye blinks as indicator for sensory irritation during constant and peak exposures to 2-ethylhexanol

Two experiments were performed to re-evaluate the sensory irritating properties of 2-ethylhexanol in relation to dose and time and to examine the usability of electromyographic eye blink recordings as indicator of sensory irritation. Mean exposure levels of 1.5, 10 and 20 ppm were realized in experimental models simulating either constant or variable 4 h exposure. Each study was carried out with two subject samples, healthy young men with self-reported multiple chemical sensitivity (sMCS) and age matched controls. Although 2-ethylhexanol exposure was below the occupational threshold limit value of 50 ppm, the study revealed strong dose–response relationships between airborne solvent concentrations and blink rates. During 40 ppm peak exposures the blink rate increased threefold. In the course of 4 h, exposure blink rates increased significantly showing no adaptation. Subjects with sMCS revealed, with one exception at start of exposure, no significantly higher blink rates than controls. The results indicate that the irritative potential of 2-ethylhexanol is higher than commonly expected. In both exposure scenarios with either constant or peak exposures, electromyographic eye blink recordings were an appropriate method for the examination of acute sensory irritations in time.     

Formaldehyde and chemosensory irritation in humans: a controlled human exposure study

OBJECTIVES: The objective of this study was to examine the possible occurrence of sensory irritation and subjective symptoms in human volunteers exposed to formaldehyde concentrations relevant to the workplace. The set up of the study included formaldehyde exposures with and without peaks, the presence and absence of a masking agent, and evaluation of the influence of personality factors. METHODS: Testing was conducted in 21 healthy volunteers (11 males and 10 females) over a 10-week period using a repeated measures design. Each subject was exposed for 4h to each of the 10 exposure conditions on 10 consecutive working days. The 2-week exposure sequences were randomized, and the exposure to formaldehyde and the effect measurements were conducted in a double-blind fashion. During 4 of the 10 exposure sessions, 12-16 ppm ethyl acetate (EA) was used as a 'masking agent' for formaldehyde exposure. Measurements consisted of conjunctival redness, blinking frequency, nasal flow and resistance, pulmonary function, and reaction times. Also subjective ratings of discomfort as well as the influence of personality factors on the subjective scoring were examined. These were carried out pre-, during and/or post-exposure, and were used to evaluate the possible irritating effects of formaldehyde at these concentrations. RESULTS: The results indicated no significant treatment effects on nasal flow and resistance, pulmonary function, and reaction times. Blinking frequency and conjunctival redness, ranging from slight to moderate, were significantly increased by short-term peak exposures of 1.0 ppm that occurred at a baseline exposure of 0.5 ppm formaldehyde. Results of the subjective ratings indicated eye and olfactory symptoms at concentrations as low as 0.3 ppm. Nasal irritation was reported at concentration levels of 0.5 ppm plus peaks of 1.0 ppm as well as at levels of 0.3 and 0.5 ppm with co-exposure to EA. However, exposure to EA only was also perceived as irritating. In addition, volunteers who rated their personality as 'anxious' tended to report complaints at a higher intensity. When 'negative affectivity' was used as covariate, the level of 0.3 ppm was no longer an effect level but 0.5 ppm with peaks of 1.0 ppm was. Increased symptom scores were reversed 16 h after the end of the exposures. CONCLUSIONS: The results of the present study indicated eye irritation as the most sensitive parameter. Minimal objective eye irritation was observed at a level of 0.5 ppm with peaks of 1 ppm. The subjective complaints of ocular and nasal irritation noted at lower levels were not paralleled by objective measurements of eye and nasal irritation and were strongly influenced by personality factors and smell. It was concluded that the no-observed-effect level for subjective and objective eye irritation due to formaldehyde exposure was 0.5 ppm in case of a constant exposure level and 0.3 ppm with peaks of 0.6 ppm in case of short-term peak exposures.     

Acute effects of acrolein in human volunteers during controlled exposure

Abstract

Context: Acrolein is a reactive aldehyde mainly formed by combustion. The critical effect is considered to be irritation of the eyes and airways; however, the scarce data available make it difficult to assess effect levels.

Objective: The aim of the study was to determine thresholds for acute irritation for acrolein.

Methods: Nine healthy volunteers of each sex were exposed at six occasions for 2?h at rest to: clean air, 15?ppm ethyl acetate (EA), and 0.05?ppm and 0.1?ppm acrolein with and without EA (15?ppm) to mask the potential influence of odor. Symptoms related to irritation and central nervous system effects were rated on 100-mm Visual Analogue Scales.

Results: The ratings of eye irritation were slightly but significantly increased during exposure to acrolein in a dose-dependent manner (p?<?0.001, Friedman test) with a median rating of 8?mm (corresponding to “hardly at all”) at the 0.1?ppm condition and with no influence from EA. No significant exposure-related effects were found for pulmonary function, or nasal swelling, nor for markers of inflammation and coagulation in blood (IL-6, C-reactive protein, serum amyloid A, fibrinogen, factor VIII, von Willebrand factor, and Clara cell protein) or induced sputum (cell count, differential cell count, IL-6 and IL-8). Blink frequency recorded by electromyography was increased during exposure to 0.1?ppm acrolein alone but not during any of the other five exposure conditions.

Conclusion: Based on subjective ratings, the present study showed?minor eye irritation by exposure to 0.1?ppm acrolein.     

A new cell-based method for assessing the eye irritation potential of chemicals: an alternative to the Draize test

Using a human corneal cell line (HCE-T cells) and 2 evaluation criteria, we developed a new alternative method to assess the eye irritation potential of chemicals. We exposed HCE-T cells to different concentrations of 38 chemicals for 1h and measured relative cell viability (RCV) as an endpoint at each concentration. Using the RCV values, we calculated the RCV50. We also exposed HCE-T cells to 3 fixed concentrations of the 38 chemicals (5%, 0.5%, and 0.05%) for 1h and measured the RCV at each concentration. Using the RCV values at 5%, 0.5%, and 0.05%, we developed a new criterion for eye irritation potential (total eye irritation score, TEIS) and estimated the ocular irritancy. We then assessed the correlation of the results of RCV50 and TEIS with those of the Draize rabbit eye irritation. Both the RCV50 and TEIS results exhibited good positive correlations (sensitivity: 80.77%, specificity: 83.33%, and accuracy: 81.58% for TEIS; sensitivity: 73.08-76.92%, specificity: 75.00%, and accuracy: 73.68-76.32% for RCV50). We conclude that the new in vitro model using HCE-T cells is a good alternative evaluation model for the prediction of the eye irritation potential of chemicals.     

Evaluation of dermal and eye irritation and skin sensitization due to carbon nanotubes

The present paper summarizes the results of our studies on dermal and eye irritation and skin sensitization due to carbon nanotubes (CNTs), whose potential applications and uses are wide and varied, including CNT-enhanced plastics, electromagnetic interference/radio-frequency (EMI/RFI) shielding, antistatic material, flexible fibers and advanced polymers, medical and health applications, and scanning probe microscopy. Skin and eyes have the highest risk of exposure to nanomaterials, because deposition of nanomaterials to the surficial organs has the potential to be a major route of exposure during the manufacturing, use, and disposal of nanomaterials. Two products composed of single-walled carbon nanotubes (SWCNTs) and two products composed of multi-walled carbon nanotubes (MWCNTs) were tested regarding acute dermal and acute eye irritation using rabbits, and skin sensitization using guinea pigs. The concentrations of the CNTs in the substances were the maximum allowable for administration. The two products of SWCNTs and one of the products of MWCNTs were not irritants to the skin or eyes. The other product of MWCNTs caused very slight erythema at 24 h, but not at 72 h, after patch removal in the dermal irritation experiments and conjunctival redness and blood vessel hyperemia at 1 h, but not at 24 h, in eye irritation experiments. These findings showed that one product of MWCNTs was a very weak acute irritant to the skin and eyes. No products of SWCNTs and MWCNTs exhibited skin-sensitization effects. Our knowledge of the toxicological effects of CNTs is still limited. Further information is needed to clarify the potential for irritation and sensitization given the complex nature of CNTs.     

Improvement of the Bovine Corneal Opacity and Permeability (BCOP) assay as an in vitro alternative to the Draize rabbit eye irritation test

Measurement of ocular irritancy is a necessary step in the safety evaluation of both industrial and consumer products. Assessment of the acute eye irritation potential is therefore part of the international regulatory requirements for testing of chemicals.The Bovine Corneal Opacity and Permeability (BCOP) assay is generally accepted as a valid in vitro alternative method to the Draize eye irritation test to detect corrosive and severe eye irritants (category 1), but has not proven sensitive enough to discriminate accurately moderate (category 2A/2B) to mild and non-irritating compounds. In the currently accepted BCOP assay, opacity is determined by the amount of light transmission through the cornea, and permeability is determined by the amount of sodium fluorescein dye that passes through all corneal cell layers. Both measurements are used to assign an In Vitro Irritancy Score (IVIS) for prediction of the in vivo ocular irritation potential of a test substance. Nowadays, opacity is measured by an OP-KIT opacitometer providing a center-weighted reading of light transmission by measuring changes in voltage when the transmission of white light passes through the cornea alters. As a consequence, this may underestimate opacity that develops as spots or heterogeneous opaque areas on the periphery of an isolated cornea.A prototype of a laser light-based opacitometer (PLLBO) allowing better measurement of opacities was developed by Van Goethem et al. (2010). This new device showed improved sensitivity to detect subtle changes in corneal transparency. Furthermore, the new opacitometer allowed the analysis of the complete corneal surface and was able to detect more efficiently opaque spots located along the sides of the excised corneas.A further improved prototype of the PLLBO was constructed in combination with a camera and a speckle noise reducer. Treatment conditions of the corneas in the cornea holders were optimized in order to mimic more the real in vivo situation. A set of test compounds with irritancy potencies especially in the mild and moderate range was tested. The improved LLBO showed some promising features which potentially could improve the usefulness of the BCOP test. Adaptation of cornea holders showed to be of limited value and only restricted to concentrations up to 15% which mimics more test conditions in industry.This 3-year research project was sponsored by the Stavros Niarchos Foundation (Greece).     

The effect of occlusive and unocclusive exposure to xylene and benzene on skin irritation and molecular responses in hairless rats

Aromatic hydrocarbons readily penetrate the skin on dermal exposure, leading to irritation, inflammation and cytotoxicity. The effects of short-term occlusive and long-term unocclusive dermal exposure to benzene and xylene on the skin irritation response (transepidermal water loss (TEWL), skin moisture content and erythema) and cytokine/chemokine expression (interleukin-1 (IL-1), tumor necrosis factor- (TNF-) and monocyte chemoattractant protein-1 (MCP-1)) were investigated in hairless rats. Occlusive dermal exposure was carried out with 230 L of the chemicals for 1 h using Hill top chambers. In unocclusive dermal exposure, 15 L of the chemicals were applied to the skin every 2 h, for 8 h a day, for 4 days. The occlusive dermal exposure revealed a clear difference in the TEWL and erythema response of these chemicals (xylene>benzene) whereas unocclusive exposure revealed similar TEWL and erythema scores for both benzene and xylene. The expression of IL-1 was elevated 2.5- and 3.8-fold in response to occlusive and unocclusive exposure, respectively, vs control (P<0.01) for both the chemicals (benzene and xylene). Similarly, TNF- levels were elevated about 2.4- and 6.0-fold as a result of occlusive and unocclusive exposure, respectively, vs control (P<0.01). These results show that unocclusive exposure induced significantly higher TNF- expression than occlusive exposure (P<0.05). The MCP-1 expression in blood was slightly elevated compared with the control group, but this increase was not statistically significant (P>0.05). Similarly, MCP levels in skin were increased approximately 1.7- and 1.8-fold by occlusive and unocclusive exposure, respectively, compared with the control group (P<0.05). Our study demonstrates that the skin irritation profiles of benzene and xylene are similar and unocclusive long-term exposure to small amounts of these chemicals can induce more skin irritation and cytokine response than occlusive exposure.     

Human chemosensory perception of methyl isothiocyanate: Chemesthesis and odor

An unpublished laboratory study by Russell and Rush (1996) showed that human subjects sense the presence of methyl isothiocyanate (MITC) via the eyes at concentrations as low as hundreds of ppb in air, with dependence upon duration of exposure. The longer the stimulation, the lower the concentrations sensed. Application of benchmark concentration (BMC10) modeling indicated a best estimate of 330 ppb by the end of 4 h. With a confidence limit (BMCL) applied, the level dropped to 220 ppb, when employing a probit model. Receptors known as TRPA1 ion channels present in trigeminal and associated peripheral afferent nerves have shown particular sensitivity to isothiocyanates. Sensitivity to these electrophiles, which occur naturally in plants (e.g., capers and mustard greens), most likely derives from a mechanism of reversible covalent bonding. Such sensing can provide warning of potential damage rather than actual damage itself. Based upon its reputation as a lachrymator, Russell and Rush assumed that the eyes would sense MITC, before the upper airways, so gathered no data from the airways, except for odor. Field results from spills and results of acute exposures to animals covered in Dourson et al. (2010) add pertinent information on the matter.     

兔角膜上皮细胞短期暴露实验替代兔眼刺激实验的可行性研究

目的：探讨用兔角膜上皮细胞（SIRC）模型对眼用制剂包装材料的浸提液进行短时暴露（STE）实验,以替代动物眼刺激实验的可行性。方法：在眼用制剂包装材料的浸提液中加入不同浓度的阳性物质,同时进行STE实验和兔眼刺激实验,比较两种实验分级的一致程度。结果：两种方法对不同浓度的阳性浸提液进行实验分级的一致程度为78．6％,统计学分析证明两种方法具有相当的一致性。以动物实验的分级为标准,STE实验的灵敏度和特异性分别为100％和80％,假阳性率为20％,假阴性率为0％。结论：SIRC的STE眼刺激实验有潜力作为眼用制剂包装材料眼刺激性实验的替代方法。     

Comparative assessment of the sensory irritation potency in mice and rats nose-only exposed to ammonia in dry and humidified atmospheres

Young adult male Wistar rats, a species commonly used in inhalation toxicity studies, and OF1 mice, a species often used in sensory irritation studies, were simultaneously nose-only exposed for 45-min to ammonia in concentrations from 92 to 1243 mg/m³. This study examined airway reflexes by the changes in respiratory patterns elicited by ammonia in either dry, steam-humidified (approximately 95% relative humidity) or aqueous aerosol containing atmospheres. This served the objective to explore whether high concentrations of anhydrous ammonia and/or high humidity and aqueous aerosol change the predominant nasal deposition site to more distal locations in the lung. Animals from all groups tolerated the exposure without evidence of respiratory tract irritation, changes in body and lung weights. The evoked changes on breathing patterns resembled those known to occur following exposure to ‘upper respiratory tract sensory irritants’, rapid in onset and reversibility. Reflex stimulation from the lower airways was not observed in any group. While mice showed some adaption during the 45-min exposure period, rats displayed more stable changes in respiratory patterns. In this species humidity- or aqueous aerosol-related changes in sensory irritation potency did not occur to any appreciable extent. The respiratory decrease 50%, RD₅₀, was 972 and 905 mg/m³ in dry and wet air, respectively. In contrast, mice appeared to more susceptible to ammonia in presence of dry air (the RD₅₀, was 582 and 732 mg/m³ in dry and wet air, respectively). In summary, it was shown that the sensory irritation potency of ammonia does not increase when inhaling wet atmospheres nor penetrates this gas into the lower airways up to 1243 mg/m³ × 45-min. The mild-to-moderate sensory irritation-related effects observed at ≈400 mg/m³ (571 ppm) × 45-min do not appear to be offensive enough to impair escape as a result of upper airway sensations. Interestingly, this rat-based estimate matches almost exactly the experienced-based RAM TRAC recommendations of 696 and 492 ppm for 30 and 60 min, respectively.     

Human exposure to bisphenol A by biomonitoring: methods, results and assessment of environmental exposures

Human exposure to bisphenol A is controversially discussed. This review critically assesses methods for biomonitoring of bisphenol A exposures and reported concentrations of bisphenol A in blood and urine of non-occupationally ("environmentally") exposed humans. From the many methods published to assess bisphenol A concentrations in biological media, mass spectrometry-based methods are considered most appropriate due to high sensitivity, selectivity and precision. In human blood, based on the known toxicokinetics of bisphenol A in humans, the expected very low concentrations of bisphenol A due to rapid biotransformation and the very rapid excretion result in severe limitations in the use of reported blood levels of bisphenol A for exposure assessment. Due to the rapid and complete excretion of orally administered bisphenol A, urine samples are considered as the appropriate body fluid for bisphenol A exposure assessment. In urine samples from several cohorts, bisphenol A (as glucuronide) was present in average concentrations in the range of 1-3 microg/L suggesting that daily human exposure to bisphenol A is below 6 microg per person (<0.1 microg/kg bw/day) for the majority of the population.     

Biological monitoring for exposure to pirimicarb: Method development and a human oral dosing study

This study has developed and validated an assay to quantify metabolites of the carbamate insecticide pirimicarb, whose residues are commonly found on a variety of food products, at levels that might be expected to arise from dietary exposure at or below the acceptable daily intake (ADI, 0.02 mg/kg).     

Inhalation and epidermal exposure of volunteers to ethylene glycol: kinetics of absorption, urinary excretion, and metabolism to glycolate and oxalate

Ethylene glycol (EG) is a widely used liquid. Limited data are published regarding inhaled EG and no data regarding transdermal EG uptake in humans. In order to gain information on the quantitative fate of EG, four male volunteers inhaled between 1340 and 1610 micromol vaporous 13C-labeled EG (13C2-EG) for 4h. Separately, three of these subjects were epidermally exposed for up to 6h to liquid 13C2-EG (skin area 66 cm2). Plasma concentrations and urinary amounts of 13C2-EG were determined by gas chromatography with mass selective detection. Additionally, plasma was assayed for 13C-labeled glycolic acid 13C2-GA) and urine for 13C2-GA and 13C-labeled oxalic acid (13C2-OA). Both EG metabolites were nephrotoxic in animals and humans and embryotoxic in rodents. 13C-labels enabled to differentiate from also determined endogenous EG, glycolic acid (GA), and oxalic acid (OA). Of 13C2-EG inhaled, 5.5+/-3.0%, 0.77+/-0.15%, and 0.10+/-0.12% were detected in urine as 13C2-EG, 13C2-GA, and 13C2-OA, respectively. The skin permeability constant of liquid EG was 2.7 x 10(-5)+/-0.5 x 10(-5)cm/h. Of the dose taken up transdermally, 8.1+/-3.2% and up to 0.4% were excreted in urine as 13C2-EG and 13C2-GA, respectively. It is calculated that equally long-lasting exposure to 10 ppm vaporous EG or wetting of both hands by liquid EG leads to about the same body burden by EG and metabolites. The amounts of GA and OA excreted daily in urine as a result of exposure (8h/day) to 10 ppm EG are about 15% and 2%, respectively, of those excreted from naturally occurring endogenous GA and OA.     

Reproductive effects in male and female rats from neonatal exposure to p-octylphenol.

A number of alkylphenolic compounds are used in a variety of commercial products and have been shown in in vitro studies to be weakly estrogenic, but in vivo data are not available addressing this issue in mammals. Human exposure to alkylphenols may occur not only from these environmental contaminants but also through contact with manufactured and metabolic breakdown products. In this study, Sprague-Dawley rats were exposed to octylphenol by oral gavage at doses of 0 (vehicle: corn oil), 12.5, 25, 50, or 100 mg/kg once daily on postnatal days 1 through 5 to examine its effects on male and female reproductive function after puberty. In addition, preputial separation and vaginal opening as endpoints of sexual maturation, estrous cycling, sperm count, serum testosterone concentration, and histopathologic changes of the reproductive organs of male and female rats were examined. Male reproductive organs were weighed at necropsy. Body weights of male and female rats exposed to octylphenol at 50 and 100 mg/kg throughout the study after the administration period, those of both sexes at 7 and 9 weeks of age in the 25 mg/kg group, and that of females at 9 weeks of age in the 12.5 mg/kg group were lower than those of controls. Significant delays in acquisition of puberty in males and females exposed to octylphenol at 50 and 100 mg/kg were observed. Estrous cycle, copulation and fertility, sperm count, and serum testosterone concentration were not affected by neonatal exposure to octylphenol. Significant decrease in absolute and relative prostate weight in the 12.5, 25, 50, and 100 mg/kg groups, and absolute epididymal weight in the 100 mg/kg group, increase in relative testes weight in the 100 mg/kg group, and relative seminal vesicle weights in the 50 and 100 mg/kg groups were found. Histopathologic analyses of reproductive organs in male and female rats exposed neonatally to octylphenol revealed no marked alterations. The results of this study indicate that early neonatal exposure to octylphenol by oral gavage did not cause dysfunction of reproductive performance (mating and fertility) in male or female rats, and no disruption of development of the reproductive tract was observed in male or female rats, while significant decreases in body weights in the 25 mg/kg and more groups, delays of sexual maturation in the 50 mg/kg and greater groups, and decrease in ventral prostate weights in all octylphenol-treated groups were found. Therefore, it is concluded that NOAEL (no-observed adverse effect level) for systemic toxicity was ≤ 12.5 mg/kg/day and that for reproductive toxicity was 100 mg/kg/day under the present experimental condition.     

Infant dietary exposure to dioxins and dioxin-like compounds in Greece

The dietary exposure of infants to polychlorinated dibenzo dioxins and furans (PCDD/Fs) and dioxin like polychlorinated biphenyls (dl-PCBs) is an issue of great social impact. We investigated for the first time the dietary intake of these compounds in infants living in Greece. We included in our study two age groups: 0–6 months, when infants are fed exclusively by human milk and/or formula milk, and 6 to 12 months, when solid food is introduced to nutrition. We took into consideration analytical results for PCDD/Fs and dl-PCBs concentrations in the most popular infant formulae in the Greek market, previous data for mother milk concentrations of PCDD/Fs and dl-PCBs from Greece, and finally analytical data for fat-containing food products from the Greek market. In the first study group, it was found than in infants exclusively fed by breast milk, the calculated sum of PCDD/Fs and dioxin-like PCBs (60.3–80.4 TEQ pg/kg body weight) was significantly higher than that of infants that consume a combination of human milk and formula (31.2–41.6 TEQ pg/kg body weight). In the second study group, separate daily intake estimations were performed for babies receiving human milk (estimated total daily intake 19.76–24.95 TEQ pg/kg body weight) and formula milk (estimated total daily intake 1.60–2.24 TEQ pg/kg body weight). The risks of this exposure should not be overestimated because nursing is restricted to a limited period of human life and besides, the potential consumption of higher levels of dioxin-like compounds is fully compensated by the significant benefits of breast-feeding.     

Reproductive effects in male and female rats from neonatal exposure to p-octylphenol

A number of alkylphenolic compounds are used in a variety of commercial products and have been shown in in vitro studies to be weakly estrogenic, but in vivo data are not available addressing this issue in mammals. Human exposure to alkylphenols may occur not only from these environmental contaminants but also through contact with manufactured and metabolic breakdown products. In this study, Sprague-Dawley rats were exposed to octylphenol by oral gavage at doses of 0 (vehicle: corn oil), 12.5, 25, 50, or 100 mg/kg once daily on postnatal days 1 through 5 to examine its effects on male and female reproductive function after puberty. In addition, preputial separation and vaginal opening as endpoints of sexual maturation, estrous cycling, sperm count, serum testosterone concentration, and histopathologic changes of the reproductive organs of male and female rats were examined. Male reproductive organs were weighed at necropsy. Body weights of male and female rats exposed to octylphenol at 50 and 100 mg/kg throughout the study after the administration period, those of both sexes at 7 and 9 weeks of age in the 25 mg/kg group, and that of females at 9 weeks of age in the 12.5 mg/kg group were lower than those of controls. Significant delays in acquisition of puberty in males and females exposed to octylphenol at 50 and 100 mg/kg were observed. Estrous cycle, copulation and fertility, sperm count, and serum testosterone concentration were not affected by neonatal exposure to octylphenol. Significant decrease in absolute and relative prostate weight in the 12.5, 25, 50, and 100 mg/kg groups, and absolute epididymal weight in the 100 mg/kg group, increase in relative testes weight in the 100 mg/kg group, and relative seminal vesicle weights in the 50 and 100 mg/kg groups were found. Histopathologic analyses of reproductive organs in male and female rats exposed neonatally to octylphenol revealed no marked alterations. The results of this study indicate that early neonatal exposure to octylphenol by oral gavage did not cause dysfunction of reproductive performance (mating and fertility) in male or female rats, and no disruption of development of the reproductive tract was observed in male or female rats, while significant decreases in body weights in the 25 mg/kg and more groups, delays of sexual maturation in the 50 mg/kg and greater groups, and decrease in ventral prostate weights in all octylphenol-treated groups were found. Therefore, it is concluded that NOAEL (no-observed adverse effect level) for systemic toxicity was ≤ 12.5 mg/kg/day and that for reproductive toxicity was 100 mg/kg/day under the present experimental condition.     

Pesticide exposure and genetic variation in xenobiotic-metabolizing enzymes interact to induce biochemical liver damage

Metabolic activation of pesticides in the liver may result in highly reactive intermediates capable of impairing various cellular functions. Nevertheless, the knowledge about the effect of pesticide exposure on liver function is still limited. This study assessed whether exposure to pesticides elicits early biochemical changes in biomarkers of liver function and looked for potential gene-environmental interactions between pesticide exposure and polymorphisms of pesticide-metabolizing genes. A longitudinal study was conducted in farm-workers from Andalusia (South Spain), during two periods of the same crop season with different degree of pesticide exposure. Blood samples were taken for the measurement of serum and erythrocyte cholinesterase activities as well as for determining clinical chemistry parameters as biomarkers of liver function. Serum lipid levels were also measured as they may help to monitor the progress of toxic liver damage. A reduction in serum cholinesterase was associated with decreased levels of all clinical chemistry parameters studied except HDL-cholesterol. Conversely, a decreased erythrocyte cholinesterase (indicating long-term pesticide exposure) was associated with increased levels of aspartate aminotransferase and alkaline phosphatase and increased levels of triglycerides, total cholesterol and LDL-cholesterol, but reduced levels of HDL-cholesterol. Changes in liver biomarkers were particularly associated with the PON1_55M/192R haplotype. The obtained results therefore support the hypothesis that pesticide exposure results in subtle biochemical liver toxicity and highlight the role of genetic polymorphisms in pesticide-metabolizing enzymes as biomarkers of susceptibility for developing adverse health effects.