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PubMed1985

Taste aversions conditioned with multiple exposures to gamma radiation: abolition by area postrema lesions in rats.

Lesions which destroy the area postrema (AP) and damage the adjacent nucleus of the solitary tract (NTS) attenuate conditioned taste aversions (CTA) induced by a variety of pharmacological agents as well as exposure to radiation. In this experiment the possibility that AP lesions might not attenuate a radiation-induced CTA, when multiple pairings of the novel taste stimulus and exposure to gamma radiation occurred, was examined. Three groups of male rats received lesions of AP and another 3 groups received sham lesion. Following a recovery period all rats were adapted to a 23.5 h/day water deprivation schedule. A sodium saccharin solution (0.1%) was offered to all rats during the regular drinking period (0.5 h) on two days per week, with water available on the other days. Access to saccharin was followed by exposure to 0, 20 or 40 rad of gamma radiation with one lesioned and one sham-lesioned group assigned to each dose level. After 4 pairings of saccharin with radiation the sham-lesioned groups exposed to 20 and 40 rad of radiation exhibited a dose-dependent aversion to the saccharin solution (P less than 0.0001), whereas the AP-lesioned groups did not differ significantly from the 0 rad sham-lesioned group. Subsequent two-bottle choice tests, which are a more sensitive measure of CTA, confirmed that the AP-lesioned rats exposed to 20 and 40 rad radiation did not develop a significant CTA relative to the two 0 rad radiation groups. Thus, AP lesions abolished the CTA normally induced by multiple pairings of saccharin with exposure to 20 or 40 rad gamma radiation.

Animals↗
PubMed2001

Transient inflammation and dysfunction of the eustachian tube secondary to multiple exposures of simulated gastroesophageal refluxant.

Gastroesophageal reflux is a common problem in the newborn and preschool periods. Recent research suggests that it may be related to eustachian tube dysfunction and otitis media with effusion. The purpose of this experiment was to investigate the relationship between simulated gastroesophageal reflux and eustachian tube dysfunction. Rat middle ears were repeatedly exposed (transtympanically) to pepsin in hydrochloric acid or to phosphate-buffered saline solution. Their eustachian tube function was evaluated by assessing passive opening and passive closing pressures, and active clearance of positive and negative pressure. The passive pressure function tests showed variable results. The rats exposed to pepsin in hydrochloric acid had an impaired ability to clear positive and negative pressure from the middle ear as compared to the rats exposed only to phosphate-buffered saline solution. The results demonstrate that multiple middle ear exposures to pepsin in hydrochloric acid leads to eustachian tube dysfunction in rats.

Animals↗
PubMed1997

Schistosoma mansoni: development and modulation of the granuloma after or multiple exposures in the baboon (Papio cynocephalus anubis).

The ability of the host to modulate the granulomatous response around ova trapped in tissues determines the severity of disease to schistosome infections. Multiple factors may affect this modulation such as age, prior sensitization, history of treatment, and exposure. The present study examines the effect of different patterns of exposure on the sequential development and modulation of granuloma in juvenile Kenyan baboons (Papio cynocephalus anubis) after receiving either a single infection (SI) of 1500 Schistosoma mansoni cercariae or multiple infections (MI) of 150 cercariae, once a week for 10 weeks. Prior to sacrifice at 17 weeks postinfection (p.i.), liver biopsies were obtained at Weeks 0, 6, 9, and 13. SI animals experienced more prolonged dysentery and greater weight loss compared to MI animals. Peak hepatic granuloma size (mean 355 +/- 65.5 microns diameter), the maximum percentage of eosinophils in the granuloma (61%), and severity of disease occurred at 6 weeks in SI animals. Peak granuloma size and pathology did not appear until Week 9 in the MI animals (mean 317.7 +/- 67.3 microns diameter). Granuloma size, tissue eosinophilia, and gross pathology diminished by Week 13 p.i. and were virtually absent in both groups by Week 17. The decrease in granuloma size, pathology, and clinical illness resolved more rapidly in the MI baboons. Singly infected baboons were more susceptible to infection (83 +/- 12% of cercariae developed into adult worms) compared to MI baboons (67 +/- 7%, P < 0.01). Eggs recovered from tissues at necropsy were primarily confined to the large intestine (85% of total egg recovered), followed by liver (10%) and small intestine (5%). Significantly more eggs were recovered from MI compared to SI animals, indicating a higher fecundity of female worms in the MI baboons. These date demonstrate that granulomatous responses develop more slowly and modulate more rapidly with repeated infection compared to a single heavy infection and suggest the type of exposure may affect the pathologic response to infection.

Animals↗
PubMed1992

Induction of ornithine decarboxylase in specific subpopulations of murine epidermal cells following multiple exposures to 12-O-tetradecanoylphorbol-13-acetate, mezerein and ethyl phenylpropriolate.

Single applications of 12-O-tetradecanoylphorbol-13-acetate (TPA), mezerein or ethyl phenylpropriolate (EPP) to mouse skin at appropriate doses cause similar degrees of hyperplasia and comparable levels of induction of epidermal ornithine decarboxylase (ODC) activity. Multiple (n = 5) treatments with these agents, in contrast, resulted in large differences in induced ODC activity (TPA much greater than mezerein greater than EPP) with no differences in the degree of hyperplasia or [3H]thymidine pulse-labeling among the multiple treatment groups. To attempt to explain the cellular basis for the greater ODC-inducing ability of TPA relative to mezerein and EPP in chronic exposure protocols, immunocytochemical and flow cytometric analyses were performed. Immunocytochemistry using an ODC-specific polyclonal antibody revealed substantially different pattern of ODC-positive cells in chronically exposed epidermis than observed with single exposures. TPA treatment resulted in very pronounced immunostaining of the perifollicular cells, with little evidence of specific staining in the interfollicular epidermis mezerein treatment yielded staining in both interfollicular and some perifollicular areas, while EPP treatment produced the least amount of specifically stained cells, all of which were in the interfollicular epidermis. Flow cytometric analysis of keratinocytes isolated from chronically treated skin identified three distinct subpopulations that bound varying amounts of ODC antibody. Chronic treatment of CD-1 murine epidermis with TPA appeared to cause the expansion of an intermediate sized cell subpopulation that was not apparent with EPP or mezerein. Our results suggest that chronic treatment of murine epidermis with the potent complete tumor promoter TPA leads to the selective expansion of a keratinocyte subpopulation that is hyperinducible for ODC and may be identical to the cells in the perifollicular region previously identified. These observations also suggest that the weaker tumor promoters mezerein and EPP are less capable of causing expansion of this specific subpopulation, which may be an important target cell population for neoplastic transformation in mouse epidermis.

Alkynes↗
PubMed1998

Multiple exposure to arsenic, antimony, and other elements in art glass manufacturing.

Art glass manufacturing is one of the most interesting examples of exposure to complex mixtures. Among the raw materials used are silica sand, borax, carbonates, nitrates of Ca, Na, K, and a great number of compounds that are mainly oxides of As, Sb, Al, Zn, Cr, Ni, Sn, Se, Cd, Mn, Cu, Co, Fe, Nd, Er, Eu, and La. In six art glass factories that use As or Sb as fining agents, the exposure to these elements was investigated in 32 workers by means of environmental and biological monitoring. Analysis was conducted by atomic absorption spectrometry (AAS) and inductively coupled plasma mass spectrometry (ICP-MS). The results confirmed that As, which is the main carcinogen in glass production, reaches high air concentrations and is generally above the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value-time-weighted average (TLV-TWA) of 10 micrograms/m3. When partly substituted by antimonial compounds, As air concentrations dropped dramatically, while the air levels of Sb (which is considered less toxic but is classified as a class 2B carcinogen by IARC) were relatively low and below the ACGIH TLV-TWA of 500 micrograms/m3. Exposure to As and Sb also differed in the three types of jobs investigated: As was high in oven chargers, Sb was higher in batch mixers, and both elements were low in makers-formers. Eleven to 18 elements were detected: arsenic, Al, Ba, Sb, Pb, and Zn were the elements most frequently measured (in tens, and in some cases hundreds, of micrograms/m3), followed by B, Li, Mn, Se, Sn, Sr, Ce, La, and Nd (in micrograms or in some cases tens of micrograms/m3. The results of biological monitoring for As, Sb, and other elements were in agreement with environmental monitoring data. We concluded that multiple detection of elements is a useful tool (or the evaluation of exposure to complex mixtures such as those used in the art glass industry and that such detection also allows a more accurate evaluation of related epidemiological data.

Antimony↗
PubMed1986

Histopathologic and antibody responses of rabbits exposed to aerosols containing spores of Aspergillus fumigatus: comparison of single and multiple exposures.

Resistance to pulmonary aspergillosis was studied in groups of rabbits exposed to aerosolized spores of Aspergillus fumigatus for 15 minutes on successive days for a total of 10, 7, or 4 exposures or a single exposure. The results of the study demonstrated that exposure of rabbits to spores for 15 minutes on 10 successive days did not result in an accumulation of viable spores in excess of those present in the lungs of rabbits exposed a single time. The tissue response in the lungs of the rabbits exposed at multiple times was more intense than that in the rabbits exposed once, but resolution of the lesions occurred similarly in terms of time and completeness of resolution. The duration of the antibody response as determined by a passive hemagglutination test and by enzyme-linked immunosorbent assay correlated with the number of exposures to spores, in that rabbits exposed 10 or 7 times to aerosolized spores remained positive longer than did those exposed fewer times. The results of the precipitin tests in agar gel were negative in all the rabbits but one.

Aerosols↗
PubMedDate not supplied

Correlation between specific immunity to a metabolite of halothane and hepatic lesions after multiple exposures.

A correlation between the use of halogenated anesthetic agents and liver necrosis is not yet established in man. In an attempt to resolve this dilemma, guinea pigs were immunized with a complex of guinea-pig albumin and trifluoroacetate (TFA), a common metabolite of halothane and fluorexene, and then exposed to halothane on multiple occasions. Histology and liver-function tests showed no difference in the incidence of liver damage between groups of animals immune to TFA with cellular immunity and untreated control animals. However, a difference in the liver enzyme levels was seen between controls and animals showing humoral immunity.

Animals↗
PubMed2006

Exposure to multiple environmental agents and their effect.

INTRODUCTION: All children are exposed to multiple physical, chemical and biological challenges that can result in adverse health effects before and after birth. In this context, the danger of multiple exposures cannot be assessed from a single-chemical approach as used in classical toxicology. AIM: To open up a 'negotiation space' for the problem of multiple exposure to environmental stressors, defined as any physical, chemical or biological entity that can induce an adverse response. In this context, two further questions obtain: to what extent can synergistic risks be assessed, and how far could potential adverse effects be prevented by enhanced regulation? METHODS: A discussion of two general approaches is taken: 1) the investigation of mixtures such as smoking or air pollution without specifying the individual agents, and 2) the investigation of individual substances with a focus on possible interactions in the context of dose to receptor. RESULTS: Although mixtures of compounds can have effects, it may not be possible to ascribe causation to a single compound. Furthermore, cumulative low-dose insult can, in some circumstances, be more toxic than a single high-dose exposure, e.g. endocrine disruptive effects of a combination of PCBs and dioxins which disrupt the thyroid hormone status; this tends to contradict elements of classical toxicology, . These cumulative insults may further combine with heavy metals and can disrupt the heme synthesis. It is possible that groups of pollutants could be used to test their cumulative capacity to multiple stress-susceptible receptor targets as is done in smoking and air pollution. This methodology could be used for further groups of potential pollutants, for example those associated with cleaning products, or cosmetics. Testing individual substances with a focus on interactions means that not only chemicals but also concurrent diseases should be taken into account. We suggest that the enhanced regulation of potential multiple stressors falls into two discrete categories. The first comprises a more precautionary approach (as demonstrated by the banning of chemicals such as some brominated flame retardants in Europe). The second comprises a more 'permissive' liberal approach involving the initial study of an individual compound, and subsequent interrogation of that compound in combination with another (as demonstrated by lowering the carcinogenicity of aflatoxin by vaccination against hepatitis B). CONCLUSIONS: It is necessary to define and study groups of multiple stressors as in US EPA's Framework for Cumulative Risk Assessment (U.S. EPA 2003). Recent increased knowledge of the greater sensitivity of the unborn baby, the infant and the child, has led to general recognition that a higher degree of precaution is now needed in regulating for multiple stressors on the young. The more liberal permissive approach proceeding from established effects of the individual exposures is becoming less acceptable now that we know that there is much we do not understand about chronic effects of stressors during the early development phases. Conflicts over which approach to take may have to be resolved through engagement and negotiation with a wide community of stakeholders. This "community of interest" may include fundamental research scientists, practicing clinical paediatricians, patient groups, and others concerned with the health and wellbeing of infants and children.

Air Pollution↗
PubMed1988

Hyperthermia-induced exencephaly in mice: effect of multiple exposures.

Pregnant LM/Bc female mice were given a 10-minute hyperthermic exposure in a 43 degrees C waterbath during the period of neural tube closure. On day 15.5 of gestation, the females were killed, and the fetuses were examined for exencephaly. Following a single treatment on day 8.0, 8.5, 8.75, or 9.0 of gestation 1.7, 13.6, 2.9, and 0.8% of the respective fetuses displayed exencephaly. With two treatments, one on each of gestational days 8.5 and 8.75, or three treatments, one on each of gestational days 8.5, 8.75, and 9.0, the percentage of exencephalic fetuses increased to 28.3 and 59.3%, respectively. The increased response to multiple treatments was not due to an increase in the number of susceptible embryos but rather was due to the increased number of treatments. The results of this study suggest that with increasing numbers of treatments, the embryo's ability to recover from the hyperthermic exposure is lessened, resulting in an increase in exencephaly.

Animals↗
PubMed2003

Cancer risks in naval divers with multiple exposures to carcinogens.

We investigated risks for cancer and the case for a cause-effect relationship in five successive cohorts of naval commando divers (n = 682) with prolonged underwater exposures (skin, gastrointestinal tract, and airways) to many toxic compounds in the Kishon River, Israel's most polluted waterway, from 1948 to 1995. Releases of industrial, ship, and agricultural effluents in the river increased substantially, fish yields decreased, and toxic damage to marine organisms increased. Among the divers (16,343 person-years follow-up from 18 years of age to year 2000), the observed/expected ratio for all tumors was 2.29 (p<0.01). Risks increased in cohorts first diving after 1960 compared to risks in earlier cohorts, notably for hematolymphopoietic, central nervous system, gastrointestinal, and skin cancer; induction periods were often brief. The findings suggest that the increases in risk for cancer and short induction periods resulted from direct contact with and absorption of multiple toxic compounds. Early toxic effects in marine life predicted later risks for cancer in divers.

Adult↗
PubMed2005

In vivo interaction of pulmonary intravascular macrophages with activated platelets in microvessels of equine lung after multiple exposures to halothane, isoflurane, and thiamylal: a comparative ultrastructural and cytochemical study.

The pulmonary intravascular macrophages (PIMs) of equines contain a unique electron-dense surface coat that is predominantly composed of lipoproteins. A single exposure of inhalatory halothane causes mobilization of the surface coat into the endocytotic system of the PIMs, followed by expansion of the Golgi apparatus and its enrichment with acid phosphatase. Simultaneously, the cells of the lymphocytic series show hyperplasia in the form of mitotic changes inside the microvascular compartment of the lung. Halothane is known to cause acute and chronic hepatotoxicity because of its biotransformation into trifluoroacytelated polypeptides. The present study was designed to examine the comparative effects of reexposures of inhalatory doses of halothane, isoflurane, and the intravenous barbiturate thiamylal sodium in ponies to evoke a stronger response in the PIMs after four exposures at increasing intervals of 1, 2, and 6 weeks. Ultrastructural and cytochemical evidence is presented that halothane induced translocation of the surface coat into the vacuolar system of the PIMs, followed by expansion of the Golgi apparatus and its enrichment with acid phosphatase. The cell membrane was thrown into extraordinary lamellipodial extensions, which enabled the PIMs to interact with platelets within the narrow confines of the pulmonary capillaries. The relationship between PIMs and platelets developed into large platelet aggregates. Isoflurane and thiamylal sodium did not affect the circulating platelets, although the surface coat was translocated into the endolysosomes in both situations. Although isoflurane is a lipid-soluble inhalant anesthetic similar to halothane, it is subject to very little biotransformation after use and in the present model demonstrates no immune response.

Acid Phosphatase↗
PubMed1987

Comparative cytogenetic analysis of bone marrow damage induced in male B6C3F1 mice by multiple exposures to gaseous 1,3-butadiene.

Groups of male B6C3F1 mice (N = 12) were exposed to ambient air or to gaseous 1,3-butadiene (BD) at 6.25, 62.5, and 625 ppm for 10 exposure days (6 hr + T90/day). Exposure to BD induced in bone marrow: 1) a significant increase in the frequency of chromosomal aberrations (CA); 2) a significant elevation in the frequency of sister chromatid exchanges (SCE); 3) a significant lengthening of the average generation time (AGT); 4) a significant depression in the mitotic index (MI); and, as measured in the peripheral blood, 5) a significant increase in the proportion of circulating polychromatic erythrocytes (%PCE), and 6) a significant increase in the level of micronucleated PCE (MN-PCE) and micronucleated normochromatic erythrocytes (MN-NCE). The most sensitive indicator of genotoxic damage was the frequency of SCE (significant at 6.25 ppm), followed by MN-PCE levels (significant at 62.5 ppm), and then by CA and MN-NCE frequencies (significant at 625 ppm). The most sensitive measure of cytotoxic damage was AGT (significant at 62.5 ppm), followed by %PCE (significant at 625 ppm), and then by MI (significant by trend test only). Because each cytogenetic endpoint was evaluated in every animal, a correlation analysis was conducted to evaluate the degree of concordance among the various indicators of genotoxic and cytotoxic damage. The extent of concordance ranged from a very good correlation between the induction of MN-PCE and the induction of SCE (correlation coefficient r = 0.9562) to the lack of a significant correlation between the depression in the MI and any other endpoint (r less than 0.37).

Animals↗
PubMed2001

Effects of multiple exposures of small doses of Pembina Cardium crude oil and diesel in rats.

In lands used for agricultural purposes, petroleum- or diesel-contaminated wastes and accidental spills of crude oil at some drilling sites pose exposure risks for occupational public, livestock, and wildlife. This study has assessed the effects of an Alberta crude oil, Pembina Cardium crude oil (PCCO), and a commercial diesel fuel #2 (CDF-2) in Sprague-Dawley rats after repeated exposures at small dose levels. Rats were given by gavage on day 1, 3, 5, and 8 specified dosages of either the control vehicle, methylcellulose (MC) (1.25 ml/kg), or PCCO (0.25-1.25 ml/kg), or CDF-2 (1.25 ml/kg). Exposure of rats to these dose levels of the test substances caused no overt symptoms of intoxication. A small but statistically significant increase in liver somatic index was observed in rats exposed to 1.25 ml/kg doses of PCCO and CDF-2; however, kidney somatic index was not significantly affected by these treatments. Blood analyses for hematological and clinical indicators of systemic impairments did not show any significant changes (p > 0.05) between the control and PCCO- or CDF-2-exposed rats. Biochemical assessment of liver and kidney tissues showed that compared to the control group, the PCCO- and CDF-2-exposed groups had a marked and significant increase (p < 0.05) in the hepatic activity of ethoxyresorufin-O-deethylase (EROD, a cytochrome P-450 [CYP] 1A1/A2-linked enzyme). In PCCO-exposed rats, the induction of EROD was dose-dependent. Exposure of rats with PCCO and CDF-2 also caused dose-related increases from the unexposed (control) or MC dosed rats in (1) hepatic activities of aryl hydrocarbon hydroxylase (AHH, a CYP 1A1-linked enzyme), ethoxycoumarin-O-deethylase (ECOD, a CYP 2B/1A-linked enzyme), glutathione transferase (GT), and NADPH-catalyzed microsomal lipid peroxidation; and (ii) ECOD activity in kidneys. The induction of hepatic CYP-linked enzymatic activities by PCCO and CDF-2 could be due to de novo synthesis of selected isoforms, as evidenced by the relative differences in the inhibition of EROD activity with 7,8-benzoflavone or metyrapone.

Animals↗