Ototoxicity in rats exposed to ethylbenzene and to two technical xylene vapours for 13 weeks

Male Sprague–Dawley rats were exposed to ethylbenzene (200, 400, 600 and 800 ppm) and to two mixed xylenes (250, 500, 1,000 and 2,000 ppm total compounds) by inhalation, 6 h/day, 6 days/week for 13 weeks and sacrificed for morphological investigation 8 weeks after the end of exposure. Brainstem auditory-evoked responses were used to determine auditory thresholds at different frequencies. Ethylbenzene produced moderate to severe ototoxicity in rats exposed to the four concentrations studied. Increased thresholds were observed at 2, 4, 8 and 16 kHz in rats exposed to 400, 600 and 800 ppm ethylbenzene. Moderate to severe losses of outer hair cells of the organ of Corti occurred in animals exposed to the four concentrations studied. Exposure to both mixed xylenes produced ototoxicity characterized by increased auditory thresholds and losses of outer hair cells. Ototoxicity potentiation caused by ethylbenzene was observed. Depending on the mixed xylene studied and the area of the concentration–response curves taken into account, the concentrations of ethylbenzene in mixed xylenes necessary to cause a given ototoxicity were 1.7–2.8 times less than those of pure ethylbenzene. Given the high ototoxicity of ethylbenzene, the safety margin of less or equal to two (LOAEL/TWA) might be too small to protect workers from the potential risk of ototoxicity. Moreover, the enhanced ototoxicity of ethylbenzene and para-xylene observed in mixed xylenes should encourage the production of mixed xylenes with the lowest possible concentrations of ethylbenzene and para-xylene.     

Potentiation of noise-induced hearing loss by low concentrations of hydrogen cyanide in rats.

Noise-induced hearing loss is the most prevalent occupational injury in the United States despite the adoption of clear permissible exposure limits and protocols for hearing conservation. This study identifies low-level chemical asphyxiant exposure as a risk factor capable of potentiating noise-induced hearing loss. Rats were exposed to 10, 30, and 50 ppm hydrogen cyanide (HCN) alone for 3.5 h (n = 28) or in combination with 2 h octave band noise exposure (100 dB(lin); n = 28). Additional groups received noise exposure alone (n = 16) and no treatment other than placement in an inhalation chamber with clean air and quiet (n = 16). Pure tone compound action potential (CAP) thresholds were determined 4 weeks following the exposure in order to assess pure tone auditory sensitivity and permanent threshold impairment. Cochleae from an additional 13 subjects were processed for light microscopy to permit assessment of hair cell loss. The results demonstrate that the noise exposure alone impaired CAP threshold by about 10 dB, averaged between 12-40 kHz, and produced a 5% loss of outer hair cells at the base of the cochlea, but no inner hair cell loss. The combined exposure to noise and HCN caused a cyanide dose-dependent CAP threshold impairment that exceeds the noise exposure alone. This effect reached statistical significance at a HCN level of 30 ppm. Combined exposure also produced more outer hair cell loss than noise alone. HCN alone did not cause significant hearing loss or hair cell loss. A risk assessment analysis was conducted for the auditory threshold data using benchmark dose software published by the U. S. EPA (BMDS version 1.3). A continuous model showed that the data could be described by a linear function. For a benchmark response corresponding to a 5 dB increase in auditory threshold above the effect of noise alone, the lower bound on the 95% confidence interval for the benchmark dose was 9 ppm. The benchmark dose that impaired auditory threshold 10% above the effect of noise alone had a lower bound of 2 ppm. The lower bound to the HCN dose that produced a 1 SD elevation in noise-induced hearing loss was 16 ppm. These exposure levels provide a range of concentrations below to slightly above the short-term exposure limit for HCN. However, if these levels are adjusted for an 8 h time-weighted average (TWA), the resulting levels are below the permissible exposure level (PEL) for HCN.     

Trimethyltin disrupts auditory function and cochlear morphology in pigmented rats

Trimethyltin (TMT) produces auditory deficits, presumably of cochlear origin, in rats. The present study identified pathological changes in the cochlea following treatment with TMT and correlated them with auditory threshold changes. Thresholds were determined by reflex-modulation audiometry, before and after treatment with TMT or with saline vehicle. Animals were then perfused and their cochleas embedded for examination as block-surface preparations or radial sections. In the first week following treatment, all TMT-treated rats showed threshold shifts of 40 to 60 dB at 40 kHz, and smaller threshold shifts (10-25 dB) at 2.5 and 10 kHz. At 3 weeks they showed threshold shifts similar to those identified one week following treatment, but with some recovery at 10 kHz. At 10 weeks, one animal showed complete recovery and three showed recovery of function at 10 but not at 40 kHz. TMT-treated animals showed losses of outer hair cells (OHC) in the basal turn of the cochlea as early as 48 hours following exposure. Comparable OHC pathology was seen at 9 days, along with some losses of inner hair cells. More extensive pathology occurred at longer survival times including the loss of type 1 spiral ganglion cells. The loss of auditory sensitivity at high frequencies was closely related to the loss of outer hair cells in the basal turn of the cochlea.     

Styrene induced alterations in biomarkers of exposure and effects in the cochlea: mechanisms of hearing loss.

It is known that styrene is ototoxic and causes cochlear damage starting from the middle turn. However, the cellular mechanism underlying styrene ototoxicity is still unclear. In this study, rats were exposed to styrene by gavage at different doses once a day for varying periods. Styrene levels in the cochlear tissues, styrene-induced permanent hearing loss, cochlear disruptions, and cell death pathways were determined. Styrene concentration in the cochlea varied along with the basilar membrane with the lowest level in the basal turn being consistent with the lowest styrene-induced threshold shift and hair cell loss in this region. After 3 weeks of exposure (5 days per week), a dose-dependent permanent hearing loss and a hair cell loss, especially in the midfrequency region, were observed. The styrene exposure at a dose of 200 mg/kg, which induced a blood level of 6.0 +/- 1.0 microg/g, caused an average of 4.4 +/- 0.5% OHC (outer hair cell) loss and 2-5 dB threshold shift in the cochlear region of 20-70% from the apex. A significant OHC loss was not observed until 7 days of exposure at a dose of 800 mg/kg. Deiters cells appeared to be the most vulnerable target of styrene. When condensed nuclei were observed in Deiters cells after a few days of styrene exposure (800 mg/kg), other cells were still intact. Apoptotic cell death appeared to be the main cell death pathway in the cochlea after styrene exposure. In the styrene-induced apoptotic OHCs, histochemical staining detected activated caspases-9 and 8, indicating that both mitochondrial-dependent pathway and death receptor-dependent pathway were involved in the styrene-induced cell death.     

Relative ototoxicity of 21 aromatic solvents

Some aromatic solvents (e.g. toluene, p-xylene, styrene, and ethylbenzene) show, in the rat, striking ototoxicity characterized by an irreversible hearing loss, as measured by behavioural or electrophysiological methods, associated with damage to outer hair cells in the cochlea of the exposed animals. To broaden the range of aromatic solvents studied concerning their potential ototoxicity and to compare their ototoxicity quantitatively, 21 aromatic solvents were administered orally by gastric intubation to Sprague-Dawley rats for 5 days/week for a 2-week period. The dose used was 8.47 mmol kg(-1) body weight day(-1). The possible ototoxicity of the aromatic solvents was evaluated by morphological investigation of the cochlea. Whole-mount surface preparations of the organ of Corti were made to quantify the number of missing hair cells (cytocochleogram). Among the 21 solvents studied, eight (toluene, p-xylene, ethylbenzene, n-propylbenzene, styrene, alpha-methylstyrene, trans-beta-methylstyrene, and allylbenzene) caused histological lesions of the organ of Corti. They differed widely in their potency. The least ototoxic solvents caused outer hair cell (OHC) loss in the middle turn of the organ of Corti. The OHC loss was slight in the first row, and greater in the second and third rows. The most ototoxic solvents caused high losses in the three rows of the outer hair cells along the entire length of the basilar membrane. There were also occasional inner hair cell (ICH) losses in the most affected animals. Although no measurements were made of the chemical concentrations reached in the blood or the brain, tentative ranking of an increasing ototoxicity of the eight aromatic solvents could be proposed on the basis of the histological losses observed-alpha-methylstyrene相似文献   

Reproductive toxicology of inhaled styrene oxide in rats and rabbits

Experiments were performed to evaluate reproductive and developmental toxicology in rats and rabbits exposed to styrene oxide by inhalation. Female rats were exposed to 100 or 300 ppm styrene oxide or to filtered air for 7 h/day, 5 days/week for 3 weeks. Extensive mortality occurred in rats that received prolonged exposure to 100 ppm styrene oxide while 300 ppm was rapidly lethal. As a result exposures were terminated in this latter group and the group was eliminated from further study. The rats of the 0 and 100 ppm groups were then mated and exposed to 0 or 100 ppm styrene oxide daily through 18 days of gestation (dg). Female rabbits were artificially inseminated and exposed for 7 h daily to 0, 15, or 50 ppm styrene oxide through 24 dg. Both of these lower concentrations used for exposure of the rabbits produced mortality of does. The rats were killed at 20 dg and the rabbits at 30 dg. Pregnant animals were examined for toxic changes including altered tissue weights and histopathologic effects. Litters were evaluated using several measures of embryotoxicity, and live fetuses were examined for external, visceral, and skeletal malformations. Exposure during gestation appeared to increase preimplantation loss in rats, and tended to increase the incidence of resorptions in rabbits. In both species, fetal weights and crown-rump lengths were reduced by gestational exposure. The incidences of ossification defects of the sternebrae aned occipital bones were increased by gestational exposure of rats to styrene oxide. These results indicate that inhalation exposures at these concentrations produce reproductive and development toxicity, as well as maternal toxicity.     

The role of cytochromes P-450 in styrene induced pulmonary toxicity and carcinogenicity.

Exposure of CD-1 mice to atmospheres of 40 and 160 ppm styrene, daily for up to 10 days, caused pulmonary toxicity characterised by focal loss of cytoplasm and focal crowding of non-ciliated Clara cells, particularly in the terminal bronchiolar region. The toxicity was accompanied by an increase in cell replication rates in terminal and large bronchioles of mice exposed for 3 days or longer. The toxicity and increased cell replication were no longer apparent after a 2-day break in exposure, but re-occurred when exposure was resumed. Similar effects were seen in mice given oral doses of 10, 100 or 200 mg/kg styrene, daily for 5 days. Increases in cell replication rates were seen in the terminal bronchioles in mice dosed with 100 and 200 mg/kg styrene, but not 10 mg/kg. Toxicity was limited to 3 to 10 animals in the 200 mg/kg group. Neither morphological nor cell proliferation effects were seen in the alveolar region of the mouse lung in any of these studies, nor were any effects observed in the lungs of CD rats exposed to 500 ppm styrene for up to 10 days. The pulmonary toxicity and increased cell division seen in mice, but not rats, correlates with the known species differences in pulmonary carcinogenicity of styrene, suggesting that the acute and chronic responses are causally related. 5-Phenyl-1-pentyne was shown to inhibit the pulmonary cytochrome P-450 metabolism of styrene in vivo. Cell replication rates in the lungs of mice treated with this inhibitor and exposed to styrene were comparable with controls demonstrating that the pulmonary effects of styrene on the mouse lung are caused by a metabolite of styrene, probably styrene oxide. The risks associated with exposure to styrene appear to correlate well with the metabolic capacity of the lung.     

Toluene ototoxicity in rats: assessment of the frequency of hearing deficit by electrocochleography.

To identify the frequency range most sensitive to toluene-induced auditory damage, the auditory function of adult Long-Evans rats exposed to 1750 ppm of toluene (6 h/day, 5 days/week, 4 weeks), was tested by recording auditory-evoked potentials directly from the round window of the cochlea. The present electrocochleographic findings do not support a specific mid- to high-frequency loss of auditory sensitivity. On the contrary, the electrophysiologic data, obtained for audiometric frequencies ranging from 2 to 32 kHz, showed a hearing deficit not only in the mid-frequency region (12-16 kHz), but also in the mid-low-frequency region (3-4 kHz). Actually, the effect of toluene was independent of the frequency in our experimental conditions. Histological analysis was consistent with electrophysiologic data because a broad loss of outer hair cells occurred in both mid- and mid-apical coil of the organ of Corti.     

Differential susceptibility of rats and guinea pigs to the ototoxic effects of ethyl benzene

The present study was designed to compare the ototoxic effects of volatile ethyl benzene in guinea pigs and rats. Rats showed deteriorated auditory thresholds in the mid-frequency range, based on electrocochleography, after 550-ppm ethyl benzene (8 h/day, 5 days). Outer hair cell (OHC) loss was found in the corresponding cochlear regions. In contrast, guinea pigs showed no threshold shifts and no OHC loss after exposure to much higher ethyl benzene levels (2500 ppm, 6 h/day, 5 days). Subsequently, a limited study (four rats and four guinea pigs) was performed in an attempt to understand these differences in susceptibility. Ethyl benzene concentration in blood was determined in both species after exposure to 500-ppm ethyl benzene (8 h/day, 3 days). At the end of the first day, blood of the rats contained 23.2+/-0.8-microg/ml ethyl benzene, whereas the concentration in guinea pig blood was 2.8+/-0.1 microg/ml. After 3 days, the concentration in both species decreased with respect to the first day, but the ethyl benzene concentration in rat blood was still 4.3 times higher than that in guinea pig blood. Thus, the difference in susceptibility between the species may be related to the ethyl benzene concentration in blood.     

Comparison of toluene-induced and styrene-induced hearing losses

Toluene and styrene are industrial solvents that can severely damage the auditory function in adult rats. In the present study, toluene (1000 to 2000 ppm) and styrene doses (500 to 1500 ppm) were investigated according to the same schedule: 6 hours per day, 5 days per week, for 4 consecutive weeks. The auditory function of the animals was tested by recording evoked potentials from the inferior colliculus over a frequency range from 2 to 32 kHz, whereas pathological data were evaluated by conventional histologic techniques. The permanent threshold shifts (PTS) were obtained with a styrene dose 2.4 times lower than that of the toluene. The slope of the regression line (PTS/doses) was 2.1 steeper with styrene than that obtained with toluene in the same experimental conditions. The sequence of histopathological events along the organ of Corti, especially the orderliness and the location of the traumas, was similar for paired concentrations of styrene and toluene, which were respectively 650 ppm, 1500 ppm for the first match, and 850 ppm, 1750 ppm for the second one. Both electrophysiological and histological findings point out the higher ototoxic potency of the styrene compared to that of the toluene. Assumptions concerning the ototoxic mechanism are addressed in the present paper.     

Evaluation of ototoxic effect of micronomicin by intravenous drip infusion

Ototoxic effect of micronomicin (MCR) in intravenous drip administration was investigated in guinea pigs (300--400 g) receiving MCR for 30 days at dose of 50 and 100 mg/kg, respectively. MCR was dissolved in physiologic saline and 1.5 ml of the solution was infused through polyethylene tube into the left external jugular vein with Perista mini-pump for 60 minutes every day after measurement of body weight. Auditory impairment was monitored by pinna reflex audiometry. Pinna reflex loss was not detected in any animal in frequency range (0.5 to 20 kHz). Cochlear hair cell damage generally was of mild degree. Two out of 6 animals treated with MCR 50 mg/kg (Table 1) showed outer hair cell loss confined to unilateral basal end and posterior 3/4 of the first turn, respectively. Outer hair cell loss was noticed in 4 of 9 animals receiving MCR 100 mg/kg (Table 2); much less extensive in 3 animals, unsymmetrical slightly extensive in remaining 1. Unilateral circumscribed loss of inner hair cells was noticed at lower part of the hook in the latter one. Vestibular hair cell loss was scattered and less extensive and occurred in 4 of the 6 50 mg/kg given animals and in 7 of the 9 100 mg/kg ones. Comparison in incidence and extension of the outer hair cell loss of the cochlea (Tables 3, 4) in the present study and previous ones on the ototoxic effect of MCR in intramuscular and intravenous administration suggests that there was no distinct difference in enhancement of the ototoxic effect in the intravenous drip administration.     

Ototoxicity of toluene in rats

Toluene is a major industrial solvent and substance of abuse which is ototoxic in rats as shown by both behavioral testing and measurement of brainstem auditory evoked response (BAER) thresholds. The objective of this investigation was to examine the morphological (hair cell loss) and functional (BAER threshold elevations) changes resulting from toluene administration. In the preliminary experiment, 5 male Sprague-Dawley rats were dosed by gavage to 0.5 ml toluene/kg body weight/day in corn oil for 21 days then consecutively to 1.0 ml toluene/kg/day for 21 days. In the main experiment, eight male Sprague-Dawley rats were dosed by gavage for eight weeks with 1.0 ml toluene/kg body weight/day in corn oil. Five and six control rats, respectively, received corn oil only. BAER thresholds were recorded from four toluene-treated and four control rats prior to dosing (main experiment) and from all rats after dosing (both experiments). Loss of outer hair cells occurred in all toluene-treated rats in the middle and basal turns of the organ of Corti, with the greatest loss in the third row and progressively less in the second and first rows. This loss was more severe in toluene-treated rats that demonstrated elevated BAER thresholds in midfrequency regions, typically 2–8 kHz. These experiments demonstrate that auditory changes are associated with cochlear hair cell loss in toluene-treated rats. These ototoxic effects of toluene contrast with those of other known ototoxicants, e.g., aminoglycoside antibiotics, in terms of the position of hair cell lesion in the organ of Corti and in the pattern of hair cell loss.     

Low-level toluene disrupts auditory function in guinea pigs

Toluene appears to have adverse effects on the human auditory system, but it is difficult to estimate its potency since it is commonly present in the workplace in combination with noise exposure; workplace noise exposures are often highly variable. Studies designed to assess toluene ototoxicity specifically have been limited to high-dose studies in a single laboratory animal model, the rat. Here permanent hearing loss has been observed at concentrations of 1000 ppm toluene and greater after inhalation exposure for 5 days, 6 h/day. The OSHA threshold limit value for toluene is only 100 ppm. The current study focuses on the onset of toluene ototoxicity acutely in the guinea pig and in adducing a mechanism of effect. In this study, evidence is presented for the impairment of auditory function by toluene in the guinea pig, at a concentration substantially lower than that used for studying permanent impairment in the rat. The impaired function was correlated with reduced energy metabolism in outer hair cells. Assessment of auditory function was made using distortion product otoacoustic emissions (DPOAE) with subsequent measurement of succinate dehydrogenase (SDH) staining density in hair cells using surface preparations. Temporary disruption of auditory function in guinea pigs is seen in subjects exposed to 250, 500, and 1000 ppm toluene for 8 h/day, 5 day/week for 1 and 4 weeks. Concentrations as low as 250 ppm toluene were able to disrupt auditory function acutely in the guinea pig, and 500 and 1000 ppm toluene produced greater acute dysfunction. SDH staining suggests that reduced enzyme activity in the midfrequency region of the cochlea occurs acutely following toluene exposure. Although the auditory dysfunction progressed between 1 and 4 weeks of exposure, a permanent loss did not develop for these subjects and hair cell death was not seen. The current study identifies early evidence of auditory system impairment in the guinea pig at low toluene concentration and evidence for impairment of energy production in hair cells. While even a transient auditory impairment has implications for workplace safety, additional study on the transition from such acute effects to permanent impairment is essential.     

灌胃α-硫辛酸对豚鼠噪声性听力损伤的防护作用研究

目的 观察自由基清除剂α-硫辛酸对噪声性听力损伤的保护作用。方法 24只体重为250~300 g的雄性纯白色豚鼠,按体重随机分为α-硫辛酸低、中、高剂量组(n=3×6)、噪声对照组(n=6)。各组动物暴露倍频程噪声(4 kHz中心频率)115 dB SPL(sound pressure level,声压级) 4 h。α-硫辛酸组动物暴露前2 d、暴露当天至暴露后7 d连续灌胃给予α-硫辛酸30 mg/(kg·d)(低剂量组)、60 mg/(kg·d)(中剂量组)、120 mg/(kg·d)(高剂量组);对照组动物相应时间灌胃给予等量的生理盐水。暴露后不同时间(3、7、10 d)测试各组动物在不同频率(8、16、24、32 kHz)下的听觉脑干反应(auditory brainstem response,ABR)值,组织学检查内外毛细胞缺失和损伤程度,以测试时的听阈值与暴露前听阈差值(听阈偏移)反映听力受损情况。结果 暴露后3 d,低、中、高剂量组在8、16 kHz频率下,与噪声对照组相比较具有显著性差异;低、高剂量组在24、32 kHz频率下与噪声对照组相比较具有显著性差异;暴露后7 d,中、高剂量组在8、16、24 kHz频率下与噪声对照组相比较具有显著性差异;低、高剂量组在32 kHz频率下与噪声对照组相比较具有显著性差异;暴露后10 d,高剂量组与噪声对照组比较具有显著性差异。组织学检查,α-硫辛酸组动物无明显内外毛细胞缺失,毛细胞形态结构破坏较轻。对照组动物内耳外毛细胞显示水肿、空泡变性等病变。结论 高、中、低剂量的α-硫辛酸对噪声性听力损伤均有一定的预防作用;高剂量的α-硫辛酸对噪声性听力损伤具有很好的预防和治疗作用。     

Differential ablation of sensory receptors underlies ototoxin‐induced shifts in auditory thresholds of the goldfish (Carassius auratus)

In recent years, fish models have become popular for investigations of ototoxic agents. However, the vast majority of such studies have focused on anatomical changes in lateral line hair cells after drug adminitration. Using the goldfish (Carassius auratus), we confirm that the acquisition of auditory evoked potentials offers a rapid and non‐invasive method for quantifying ototoxin‐induced changes in hearing sensitivity. Gentamicin (100 mg ml^?1) was the drug of choice as it is a well‐studied human ototoxin. Auditory threshold elevation was observed between 300 and 600 Hz and was accompanied by significant reductions in hair cell ciliary bundle densities in specific regions of the utricle and saccule. The correlations between structure and function suggest that differential susceptibility of sensory hair cells to acute gentamicin treatment underlies the frequency‐specific elevation of auditory thresholds. We propose that fish auditory systems should be used alongside the lateral line, for the assessment of ototoxicity in new‐developed drugs. Copyright © 2010 John Wiley & Sons, Ltd.     

Inhalation Toxicity of Sulfuryl Fluoride in Rats and Rabbits

Inhalation Toxicity of Sulfuryl fluoride in Rats and Rabbits.EISENBRANDT, D. L., AND NITSCHKE, K. D. (1989). Fundam Appl.Toxicol 12, 540–557. The inhalation toxicity of the structuralfumigant sulfuryl fluoride (SO₂F₂) was evaluated in rats andrabbits. Exposures for a preliminary 2-week study were 6 hr/day,5 days/week, to 0, 100, 300, or 600 ppm SO₂F₂ Nine often ratsat 600 ppm died or were moribund between the second and sixthexposures. Extensive kidney lesions were present in all ratsexposed to 600 ppm, whereas only minimal renal changes werenoted in rats at 300 ppm. Upper and lower respiratory tissueswere inflamed in the single rat that survived the 2-week exposureto 600 ppm. Rabbits exposed to 600 ppm SO₂F₂ were hyperactiveand one animal had a convulsion. Exposure to 300 or 600 ppmfor 2 weeks resulted in vacuolation and/or malacia in the cerebrumof all rabbits and most of these rabbits also had moderate inflammationof nasal tissues; a few rabbits at 600 ppm had inflammationof the trachea or bronchi. A subsequent 13-week study evaluatedrats and rabbits exposed to 0, 30, 100, or 300 ppm SO₂F₂ (337ppm TWA for rabbits). Rabbits initially were exposed to a highconcentration of 600 ppm; however, convulsions were noted intwo animals after nine exposures and the concentration subsequentlywas reduced to 300 ppm. Vacuolation and/or malacia were observedin the cerebrum of all rabbits at the highest concentration;one rabbit exposed to 100 ppm also had cerebral vacuolation.Rabbits at the highest concentration, as well as one rabbitexposed to 100 ppm, had inflammation of the nasal tissues. Ratsexposed to 300 ppm SO₂F₂ for 13 weeks had mottled incisor teeth,minimal renal effects, pulmonary histiocytosis, inflamma tionof nasal tissues, and cerebral vacuolation. Also, rats exposedto 100 ppm SO₂F₂ for 13 weeks had mottled teeth. fluoride toxicitywas suggested by mottled teeth in rats as well as elevationof serum fluoride levels in rats and rabbits exposed to SO₂F₂for 13 weeks. Although repeated exposure of rats and rabbitsto 100–600 ppm SO₂F₂ resulted in toxicity ofthe kidneys(rats only), brain, and respiratory system, no effects weredetected in animals exposed to 30 ppm for 13 weeks.     

Embryo- and fetotoxicity of inhaled chloroform in rats

This study evaluated the effects of inhalation of subanesthetic concentrations of chloroform on rat embryonal and fetal development. Pregnant Sprague-Dawley rats were exposed to 30, 100 or 300 ppm chloroform for 7hr/day on days 6 through 15 of gestation. Exposure to chloroform caused an apparent decrease in the conception rate and a high incidence of fetal resorption (300 ppm), retarded fetal development (30, 100, 300 ppm), decreased fetal body measurements (30, 300 ppm) and a low incidence of acaudate fetuses with imperforate anus (100 ppm). Chloroform was not highly teratogenic but was highly embryotoxic. The results of this study disclosed no relationship between maternal toxicity and embryo or fetotoxicity as the result of exposure to chloroform by inhalation.     

Developmental toxicity of two trimethylbenzene isomers, mesitylene and pseudocumene, in rats following inhalation exposure.

The developmental toxicity of two trimethylbenzene isomers, mesitylene (1,3,5-trimethylbenzene) and pseudocumene (1,2,4-trimethylbenzene) was studied in Sprague-Dawley rats following inhalation exposure. Pregnant rats were exposed whole body to vapours of mesitylene (0, 100, 300, 600, and 1200 ppm) or pseudocumene (0, 100, 300, 600, and 900 ppm), 6h/day, on gestational days (GD) 6 through 20. Significant decrease in maternal body weight gain and food consumption was observed at concentrations of 300 ppm mesitylene, 600 ppm pseudocumene, or greater. Fetal toxicity, expressed as significant reduction in fetal body weight, occurred at 600 and 1200 ppm mesitylene, and at 600 and 900 ppm pseudocumene. There was no evidence of embryolethal or teratogenic effects following inhalation exposure to either of these chemicals. In summary, the no-observed-adverse-effect-level (NOAEL) for maternal toxicity was 100 ppm for mesitylene and 300 ppm for pseudocumene, and the NOAEL for developmental toxicity was 300 ppm for mesitylene and pseudocumene.     

Subchronic neurotoxicity in rats of the structural fumigant, sulfuryl fluoride

Inhalation exposure of male and female Fischer 344 rats to sulfuryl fluoride [Vikane (Dow Chemical Company) gas fumigant] at 300 ppm for 6 hr/day, 5 days week, for 13 weeks caused diminished weight gain, dental fluorosis, a slight decrease in grooming, decreased flicker fusion threshold, slowing of flash, auditory and somatosensory evoked potentials, mild nasal and pulmonary inflammation, mild kidney effects, and mild vacuolation in the brain. Auditory brainstem responses (ABRs) and brain histology were evaluated two months postexposure in 2 male and 2 female rats. Both the ABRs and brain histology were within normal limits at this time, indicating that these treatment effects were, to at least a great extent, reversible. Exposure to 100 ppm resulted in dental fluorosis and very minor slowing of some evoked responses; all other measures, including brain histology, were normal. No treatment effects were noted at 30 ppm.     

Effect of inhaled industrial chemicals on systemic and local immune response

Using immunotoxic functional tests, namely IgM response to sheep red blood cells (SRBCs) and interferon-gamma (IFN-gamma) production, this study simultaneously evaluated the effects of inhaled chloroform (10, 20, and 50 ppm), carbon tetrachloride (100, 200, and 300 ppm), 1,1-dichloroethylene (5, 10, and 15 ppm), and styrene (100, 200, and 300 ppm) on the systemic (spleen) and local (lung-associated lymph nodes) immune response. At least one concentration of all the chemicals studied provoked a statistically significant increase in IgM response in the lymph nodes compared with the controls, as expressed by the number of plaque-forming cells (PFCs), whereas only the highest concentration of 1,1-dichloroethylene provoked an increase in the number of PFCs statistically different from the controls in the case of the spleens. The release of IFN-gamma in the lymph node cell cultures of the exposed mice exceeded that of the controls by more than 600%, whereas the release of IFN-gamma in the spleen cell cultures of the exposed mice was moderately different from the controls. It would appear from these results that the lung-associated lymph nodes are sensitive targets for chemical inhalation and that the results of systemic tests in the spleen may not mirror local immune response dysfunction. For risk assessment of inhaled chemicals, it is therefore important to take the local immunotoxic effects into consideration, in particular immunostimulation which may be involved in the rise in allergic diseases in industrialised countries.