Cumulative Exposure Dose Research Articles

Is exposure to endocrine disrupting compounds during fetal/post-natal development affecting the reproductive potential of farm animals?

Concerns have been raised about the potential adverse effects on reproductive health and immune status of farm animals following exposure to a range of natural and synthetic environmental compounds that disrupt normal hormonal actions. These compounds range from natural plant oestrogens (e.g. genistein, coumesterol) and mycoestrogens (e.g. Aflatoxins, zearalenone) to growth promoting pharmaceuticals (e.g. trenbolone acetate, melengastrol acetate) to chemicals spread in water, sewage sludge or the atmosphere such as detergents and surfactants (e.g. octylphenol, nonylphenol), plastics (e.g. bisphenol-A, phthalates), pesticides (e.g. methoxychlor, dieldrin, DDT) and industrial chemicals (e.g. PCB, TCDD). These compounds are commonly termed ‘endocrine disrupting compounds’ (EDCs) or ‘endocrine disruptors’ due to their ability to act as either hormone agonists or antagonists or the ability to disrupt hormone synthesis, storage or metabolism. A similar group of compounds are called ‘immunotoxicants’ and are thought to affect the immune system mainly by disrupting B and T cell homeostasis. As more studies are performed it is becoming clear that many compounds can directly or indirectly affect both the endocrine and immune systems. The susceptibility of target tissues is related to the stage of development, the cumulative exposure dose and the immune status of the individual. While some of the effects of the EDCs on the endocrine and immune systems are quite distinct, many are subtle and identifying the causative agent from the vast array of environmental challenges including EDCs, nutrition, temperature, etc. can be problematic. Identifying the causative agent is confounded by the possibility that effects that are observed in the adult may be due to exposure to EDCs during fetal life. This has major implications for the determination of universal end-point measurements to assess exposure to EDCs in farm animals.

21q22 balanced chromosome aberrations in therapy‐related hematopoietic disorders: Report from an International Workshop†

The International Workshop on the relationship between prior therapy and balanced chromosome aberrations in therapy-related myelodysplastic syndromes (t-MDS) and therapy-related acute leukemia (t-AL) identified 79 of 511 (15.5%) patients with balanced 21q22 translocations. Patients were treated for their primary disease, including solid tumors (56%), hematologic malignancy (43%), and juvenile rheumatoid arthritis (single case), by radiation therapy (5 patients), chemotherapy (36 patients), or combined-modality therapy (38 patients). 21q translocations involved common partner chromosomes in 81% of cases: t(8;21) (n = 44; 56%), t(3;21) (n = 16; 20%), and t(16;21) (n = 4; 5%). Translocations involving 15 other partner chromosomes were also documented with involvement of AML1(CBFA2/RUNX1), identifying a total of 23 different 21q22/AML1 translocations. The data analysis was carried out on the basis of five subsets of 21q22 cases, that is, t(8;21) with and without additional aberrations, t(3;21), t(16;21), and other 21q22 translocations. Dysplastic features were present in all 21q22 cases. Therapy-related acute myeloid leukemia (t-AML) at presentation was highest in t(8;21) (82%) and lowest in t(3;21) (37.5%) patients. Cumulative drug dose exposure scores for alkylating agents (AAs) and topoisomerase II inhibitors indicated that t(3;21) patients received the most intensive therapy among the five 21q22 subsets, and the median AA score for patients with secondary chromosome 7 aberrations was double the AA score for the entire 21q22 group. All five patients who received only radiation therapy had t(8;21) t-AML. The median latency and overall survival (OS) for 21q22 patients were 39 and 14 months (mo), compared to 26 and 8 mo for 11q23 patients, 22 and 28 mo for inv(16), 69 and 7 mo for Rare recurring aberrations, and 59 and 7 mo for Unique (nonrecurring) balanced aberration (latency P < or = 0.016 for all pairwise comparisons; OS, P < or = 0.018 for all pairwise comparisons). The percentages of 21q22 patients surviving 1 year, 2 years, and 5 years were 58%, 33%, and 18%, respectively. Noticeable differences were observed in median OS between 21q22 patients (n = 7) receiving transplant (BMT) (31 mo) compared to 21q22 patients who received intensive non-BMT therapy (n = 46) (17 mo); however, this was nonsignificant because of the small sample size (log-rank, P = 0.33). t-MDS/t-AML with balanced 21q22 aberrations was associated with prior exposure to radiation, epipodophyllotoxins, and anthracyclines, dysplastic morphologic features, multiple partner chromosomes, and longer latency periods when compared to 11q23 and inv(16) t-MDS/AML Workshop subgroups. In general, patients could be divided into two prognostic risk groups, those with t(8;21) (median OS, 19 mo) and those without t(8;21) (median OS, 7 mo) leukemia (log-rank, P = 0.0007).

Glycophorin A mutant frequency in radiation workers at the nuclear power plants and a hospital

We studied to assess the validity of the glycophorin A (GPA) mutant assay as a biological marker of the cumulative effects of chronic low doses of ionizing radiation. In 144 nuclear power plants workers and 32 hospital workers, information on confounding factors, such as age and cigarette smoking, was obtained through a self-administered questionnaire. The information on physical exposure doses was obtained from the registries for radiation exposure monitoring and control at each facility. The range of cumulative exposure doses were 0–12.02 cGy. GPA mutant assay was performed by the BR6 method with modification using a FACScan™ flow cytometer. Potential confounders, such as, age and cigarette smoking habits showed increasing trends with GPA variants, but were not of statistical significance. The hospital workers showed higher frequency of the GPA NO variant than nuclear power plant workers. Significant dose–response relationships were found between cumulative exposure to radiation and variants levels by simple and multiple linear regression models. The slope of regression equation of the dose–response of nuclear power plants workers was much smaller than that of hospital workers. These findings suggest that there may be dose-rate effects. In a population exposed to chronic low-dose radiation, the GPA assay shows potential to be used as an effective biologic marker for assessing the cumulative exposure dose although it could not be able to see a dose relation below 10 cGy of cumulative exposure dose.

Exposure to silica and silicosis among tin miners in China: exposure-response analyses and risk assessment

OBJECTIVESTo investigate the risk of silicosis among tin miners and to investigate the relation between silicosis and cumulative exposure to dust (Chinese total dust and respirable crystalline silica dust).METHODSA cohort...

Modeling effects of moisture content and advection on odor causing vocs volatilization from stored swine manure

Two models for evaluating the contents and advection of manure moisture on odor causing volatile organic compounds (VOC‐odor) volatilization from stored swine manure were studied for their ability to predict the volatilization rate (indoor air concentration) and cumulative exposure dose: a MJ‐I model and a MJ‐II model. Both models simulating depletion of source contaminant via volatilization and degradation based on an analytical model adapted from the behavior assessment model of Jury et al. In the MJ‐I model, manure moisture movement was negligible, whereas in the MJ‐II model, time‐dependent indoor air concentrations was a function of constant manure moisture contents and steady‐state moisture advection. Predicted indoor air concentrations and inhaled doses for the study VOC‐odors of p‐cresol, toluene, and p‐xylene varied by up to two to three orders of magnitude depending on the manure moisture conditions. The sensitivity analysis of both models suggests that when manure moisture movement exists, simply MJ‐I model is inherently not sufficient to represent a more generally volatilization process, which can even become stringent as moisture content increases. The conclusion illustrates how one needs to include a wide variety of manure moisture values in order to fully assess the complex volatilization mechanisms that are present in a real situation.

Exposure-response relations for self reported asthma and rhinitis in bakers

OBJECTIVESTo explore relations between two estimates of exposure to inhalable flour dust, and the incidence rates (IRs) of asthma and rhinitis in bakers.METHODSThis was a retrospective cohort study among 2923...

A study of multiple biomarkers in coke oven workers--a cross-sectional study in China.

We conducted a cross-sectional molecular epidemiological study of coke oven workers exposed to the established carcinogen polycyclic aromatic hydrocarbons (PAHs) to evaluate the relationships between both traditional 'exposure markers' and a series of biomarkers, including urinary 1-hydroxypyrene as a marker of internal dose, leukocyte aromatic DNA adducts as markers of biologically effective dose, serum p53 protein as a response marker and genetic polymorphisms of cytochrome P4501A1 and glutathione S-transferase MI as susceptibility markers. Twenty-five male subjects each were randomly selected from the top, middle and bottom work areas of the oven, and the control plant. They were matched for age and smoking status. The mean levels of PAH exposure, monitored by stationary and personal samplers, and of worker urinary 1-hydroxypyrene differed significantly between the top, middle and bottom of the oven and control work areas. The highest stationary and personal PAH concentrations and 1-hydroxypyrene levels were demonstrated at the top work area. Good correlations were found between the stationary PAH levels, personal PAH levels and urinary 1-hydroxypyrene levels. No positive correlations were demonstrated between aromatic DNA adduct levels and current or cumulative PAH exposure dose. In the presence of genetic polymorphisms of cytochrome P4501A1, a positive correlation was demonstrated between aromatic DNA adducts and urinary 1-hydroxypyrene levels. There was also a significant correlation between serum p53 protein levels and the cumulated benzo[a]pyrene exposure dose. Although these biomarkers have certain limitations, they are applicable to cancer epidemiology, and may contribute to our understanding of the mechanisms of carcinogenesis.

Pulmonary Function in Jute Dust‐Exposed Workers: A Dose‐Response Relationship

Pulmonary Function in Jute Dust‐Exposed Workers: A Dose‐Response Relationship: Jie Chen, et ai. Department of Pneumoconiosis, China Medical University School of Preventive Medicine—Pulmonary function tests were carried out on 488 jute‐exposed workers in a jute mill and 332 control workers. An industrial hygiene survey was also conducted. Most workers in the mill were exposed to dusts containing less than 6% silica, whereas a few workers were exposed to dusts containing approximately 10‐16% silica. The cumulative dose of dust exposure [dust level (mg/m3) X exposure year (yr)] was used as an exposure index to relate pulmonary function injury in jute workers. The results showed that jute workers had lower percentages of predicted pulmonary function than those of control workers. As the cumulative dose of dust exposure increased, average levels of pulmonary function (FVC, FEV1, MMF, V50, V25) in smoking male jute workers and V50, V25 in nonsmoking female jute workers significantly declined, and pulmonary function abnormalities (less than 80% of predicted FEVt or less than 70% of predicted V50) significantly increased as the cumulative dose of dust exposure increased. Examination of the effects of dust exposure and smoking on pulmonary function injury showed that not smoking but jute dust exposure was a factor associated with the decline in pulmonary function; Moreover, smoking interacted with dust exposure in causing declines in FEV1 Our results demonstrated that there is a dose‐response relationship between dust exposure and pulmonary function injury in jute workers. Based on this dose‐response relationship and by using the life‐table method, an exposure limit for jute dust was proposed as 4 mg/m3.

Neuroleptic-Related Dyskinesias in Autistic Children: A Prospective, Longitudinal Study

To report results from a long-term prospective study of safety of haloperidol treatment and prevalence of haloperidol-related dyskinesias. Subjects were children with autism requiring pharmacotherapy for target symptoms. After baseline assessments, children received haloperidol treatment; responders requiring further treatment were considered for enrollment into the present study. Six-month haloperidol treatment periods were followed by a 4-week placebo period. The procedure was repeated if further haloperidol treatment was required. At specified times children were evaluated by using multiple instruments. Between 1979 and 1994, 118 children aged 2.3 to 8.2 years participated in the study. The mean dose of haloperidol was 1.75 mg/day. Mainly withdrawal dyskinesias (WD) developed in 40 (33.9%) children; 20 had more than one dyskinetic episode. A subgroup that remained significantly longer in the study and had a significantly higher cumulative dose of haloperidol evidenced a significantly higher incidence of WD. Occurrence rates of tardive dyskinesia (TD) and multiple episodes of TD/WD were higher among girls. Female gender and pre- and perinatal complications may be involved in susceptibility to dyskinesias; greater cumulative haloperidol dose and/or longer exposure to haloperidol may increase the risk.

Relative risk and excess rate models in exposure-response analysis.

The cumulative dose of an environmental exposure and age are usually correlated. It is shown that if an excess rate model is the true relationship, a relative risk model based on standardized mortality ratios (SMR) may show a biased and even contradictory dose-response relationship if the incidence rate in the reference population increases rapidly by age. The choice of model should be based on biological plausibility rather than on available software, and in many cases it may be reasonable to analyze the data both according to a relative and to an excess risk model as the prior knowledge rarely favors one of these models. In a review of a volume of this journal, there were eight cohort studies analyzing dose-response relationship by comparing SMRs without reporting or analyzing excess rates. Thus, there seems to be some lack of awareness of the possible bias in analyzing exposure-disease associations by SMRs.

Electron beam induced deposition from W(CO)6 at 2 to 20 keV and its applications

Electron beam induced deposition from W(CO)6 was studied for beam energies between 2 and 20 keV and a range of exposure doses, to investigate the dependence of deposit thickness and electrical conductivity on energy and the dependence of deposit conductance on cumulative exposure dose. Larger deposited thicknesses and higher conductivities were produced at the lower beam energies and were attributed to the higher secondary electron yield at lower energies. The deposit thickness was found to scale linearly with exposure dose. The initial dependence of conductance on exposure dose (and deposit thickness) was nonlinear and was attributed to the change from a discontinuous to a continuous film, and to increased backscattering. The subsequent dependence of conductance on exposure dose was linear for deposit thicknesses which were small compared with the electron range, implying that burial precludes the further decomposition of partially decomposed W(CO)6 molecules incorporated in the deposit. Transmission electron microscope examination showed that the structure of the deposits depended on the beam scanning conditions. Deposits were used to form a mask for CF4 plasma etching of Si, while deposits on a doped GaAs substrate were found to form a Schottky contact with an ideality factor of 1.40, enabling the repair of a metal–semiconductor field-effect transistor gate to be demonstrated.

The Phototumorigenic Potential of Broad-Band (270–350 nm) and Narrow-Band (311–313 nm) Phototherapy Sources Cannot Be Predicted by Their Edematogenic Potential in Hairless Mouse Skin

The new Philips TL01 narrow-band (311-313 nm) and conventional broad-band (e.g., Philips TL12; 270-350 nm) sources are effective for psoriasis phototherapy, for which treatment regimens are based on a predetermined minimal erythema dose. TL01 phototherapy treatment times are approximately half those with TL12 for psoriasis, whereas the cumulative exposure doses at clearing are similar. We compared the phototumorigenic potential of TL01 and TL12 radiation in mouse skin. Groups of albino Skh-1 hairless mice were exposed for 5 d/week at three dose levels. At each dose level, TL12 and TL01 doses were equally edematogenic. At each dose level, TL01 radiation was significantly more effective at producing first tumors of 1 mm in diameter and multiple tumors. At the lower two dose levels, TL01 radiation produced a significantly greater proportion of squamous cell carcinomas. This study demonstrates that TL01 radiation is more phototumorigenic than TL12 radiation at equally edematogenically weighted doses. This is in contrast with previous reports that edema production by polychromatic sources is predictive of their phototumorigenic effect in Skh-1 mice. The absolute cumulative TL12 dose needed to induce tumors was much less than that for TL01 radiation. The possibility of increased tumor risk with TL01 phototherapy should be considered but must be balanced against the high phototherapeutic efficacy of this source, short treatment times, and the low cumulative doses necessary for clearing of psoriasis.

Retrospective assessment of solvent exposure in paint manufacturing.

This paper describes how exposure to solvents at two large paint making sites was assessed in a study carried out to investigate the possibility of neuropsychological effects resulting from long term exposure to organic solvents. A job exposure matrix was constructed by buildings and year. A detailed plant history was taken and this was used to identify uniform exposure periods during which workers' exposure to solvents was not thought to have changed significantly. Exposure monitoring data, collected by the company before the study, was then used to characterise exposure within each uniform exposure period. Estimates were made for periods during which no air monitoring was available. Individual detailed job histories were collected for subjects and controls. The job histories were used to estimate exposure on an individual basis with the job exposure matrix. Exposure was expressed as duration, cumulative dose, and intensity of exposure. Classification of exposure by duration alone was found to result in misclassification of subjects.

Occupational exposure and dose over time: limitations of cumulative exposure.

Cumulative exposure (average intensity times duration) is one of the most common summary measures for exposure used in occupational epidemiology. Its utility for describing quantitative exposure-effect relationships is based on several interlocking assumptions about the processes relating exposure to tissue dose, and tissue dose to adverse effects. The pharmacokinetic relationship between cumulative exposure and tissue dose was examined with models for two common exposures: inhalation of insoluble, respirable particles, and toxic metabolites of a nonpolar organic solvent. It was found that the assumption of a linear relationship between cumulative exposure and tissue dose was violated for typical exposure intensity for both substances. This caused strong nonlinear exposure-tissue dose relationships and variability in the relationship. The findings provide a possible explanation for the common observation of a disproportionately high risk of pulmonary effects for workers with relatively short, intense dust exposures, and for the finding that workers exposed to metabolically activated organic agents have a risk that is related to years of exposure but not to intensity.

Modulation of noise-potentiated acoustic startle via the benzodiazepine--gamma-aminobutyric acid receptor complex.

Diazepam (DZ), an anxiolytic benzodiazepine (BZD) compound, attenuated the facilitation of the acoustic startle response by background noise. In Experiment 1, using a cumulative dosing paradigm, the effect of DZ on noise potentiation was found to be dose related. In Experiment 2, using a between-animals exposure design, the effect of DZ on noise potentiation was attenuated by coexposure to the central-type BZD receptor antagonist RO 15-1788, which itself was without effect. Using a cumulative dosing design in Experiment 3, RO 15-1788 was found to reverse the effect of DZ, whereas the peripheral-type BZD receptor ligand RO 54864 was without effect. The differences in the effect of cumulative exposure versus single dose exposure to RO 15-1788 were interpreted as indicative of either an intrinsic effect of the antagonist after repeated exposure or an influence of background noise itself on the BZD-gamma-aminobutyric acid receptor complex.

Effects of Formaldehyde on the Nasal Mucosa

To investigate health effects of long-term exposure to formaldehyde a cross-sectional field study was performed. Seventy formaldehyde-exposed workers were compared with a control group. A higher frequency of symptoms from upper and lower airways, headache, and dermal discomfort was found in the formaldehyde-exposed group. Further, formaldehyde-exposed workers showed disturbances of nasal physiologic conditions, such as slow nasal clearance, impairment of the sense of smell, more pronounced nasal mucosal swelling, and by spirometry lower forced vital capacity than expected was found. Nasal biopsies from the concha media showed more frequent histologic changes such as loss of cilia and metaplasia in the formaldehyde-exposed group. Histologic lesions did not correlate to current or cumulative exposure doses to formaldehyde. In an experimental study of Sprague-Dawley rats exposed to formaldehyde (12.7 mg/m3, 6 hours/day, 5 days/week for 24 months), one rat developed a squamous cell carcinoma in the nose and another nasal dysplasia and in seven other rats pronounced nasal metaplasia was seen in the nasal mucosa. In a control group of rats no significant histologic lesions were found.

Infant exposure assessment for breast milk dioxins and furans derived from waste incineration emissions.

Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) have been detected in human milk samples obtained in several countries. Possible sources include emissions from incineration of municipal waste in resource recovery facilities. A formula is presented for calculating the infant daily dose of dioxin equivalents from breast milk on the basis of the maternal daily intake. Application of the formula suggests that an infant breast-fed for 12 months would receive around 10% of the cumulative exposure dose per body weight that would be received by an adult with 50 years of exposure. Further analysis indicated that the contribution of dioxin equivalents from breast milk to an infant's body concentration at the end of 12 months of breast feeding would amount to 1.7 times the concentration in the mother. However, dioxin and furan emissions from a source calculated to result in worst-case lifetime cancer risks of the order of 1 in 100,000 are only likely to increase breast milk concentrations by around 1%-10% of the levels that have been detected in several countries. This finding suggests that there are major sources of dioxins and furans other than from municipal solid waste incineration that need to be identified.

Asbestos exposure dose-bronchoalveolar milieu response in asbestos workers and the sheep model: evidences of a threshold for chrysotile-induced fibrosis.

Epidemiological studies of asbestos workers have proposed a linear dose-response relationship between asbestos cumulative exposure indices and the incidence of asbestos-related lung diseases. However, for chrysotile, several studies have not observed such a linear relationship in low exposure workers. To further study the relationship of chrysotile exposure dose - lung tissue response, we designed in the sheep model one experiment of one exposure at variable intensity and one experiment with variable rates of individual exposures. In the first study, 6 groups of 6 sheep were exposed to either 0, 1, 10, 25, 50 or 100 mg chrysotile in 100 ml saline and lung lavage analyses carried out at day 0, 12, 24, 40 and 60 after. Histopathology was done at day 60. In the second experiment, 4 groups of 12 sheep were exposed to 100 ml saline every week or every two weeks, 100 mg chrysotile in 100 ml saline every week or every two weeks. In the second experiment, lung damage was assessed by changes in vital capacity (VC), lung compliance (Cst) and profusion of chest radiographic opacities (PO). On BAL in the control sheep, there were small and transient early increases in total cells/ml, macrophages/ml, neutrophils/ml, lactate dehydrogenase (LDH)/ml, alkaline phosphatase (AK)/ml, beta-glucuronidase (beta G)/ml and procollagen lll/ml. In the 1, 10, 25, and 50 mg asbestos sheep groups, there were no significant differences. However, in the 100 mg asbestos sheep, there were significant sustained increases in total cells/ml (3-6 times controls), macrophages/ml (2-6 times controls), neutrophils/ml (60-600 times controls), LDH/ml (5-10 times controls), AK/ml (1.5-2 times controls), beta G/ml (3-5 times controls), procollagen lll/ml (2 times controls) and IgG (1.5-3 times controls). These data were correlated with histopathological findings. In the sheep exposed weekly to chrysotile, significant changes in VC, Cst and PO occurred at mean cumulative exposure dose of 1.2 g whereas in the sheep exposed every 2 weeks, similar changes in VC, Cst and PO occurred at the cumulative exposure dose of 3.6 g (P less than 0.05). In conclusion, our data suggest that there is a threshold for chrysotile-induced fibrosis. This level cannot be considered adequately in term of cumulative exposure dose but must take into account intensity and rate of individual exposures.

Status of ultraviolet A dosimetry in methoxsalen plus ultraviolet A therapy

The carcinogenic risk of methoxsalen plus ultraviolet A treatment (PUVA) is almost certainly related to the cumulative UVA exposure dose. A reliable estimate of UVA dose is a major component, therefore, in determining the long-term safety of this treatment modality. Thirty-one UVA meters from twenty-nine different PUVA treatment centers were compared with a calibrated UVA meter. The results inferred that 95% of UVA meters used in PUVA centers are reading between 57% and 159% of the true UVA irradiance, a factor of 2.8 in relative sensitivity. This wide variation in accuracy between the UVA meters gives cause for concern. These variations were attributed to differences in calibration procedure, optical properties of the sensors, and, most importantly, poor quality control by the manufacturers. The situation that appears to have existed since the introduction of PUVA therapy can be improved only if dermatologists agree that the present inaccurate and uncertain approach to UVA measurements is unsatisfactory. Manufacturers of UVA meters should be encouraged to provide instruments as reliable as the dosimeters used in radiotherapy, in which the prescribed dose is probably within 5% of the true value. Ideally, a standard type of UVA meter with appropriate physical properties and an agreed calibration procedure should be used by all centers engaged in PUVA treatment.

Combined methotrexate-PUVA therapy in the treatment of psoriasis

Thirty patients with psoriasis were treated with a 3-week course of methotrexate followed by a combination of PUVA therapy and methotrexate. When lesions cleared to less than 1% UVA-exposed body involvement, the methotrexate was stopped and PUVA therapy alone was used as maintenance therapy. This protocol achieved clearance of disease in twenty-eight of the thirty patients in a mean of 5.7 (+/- 1.0) weeks, with 9.3 (+/- 3.0) exposures to PUVA therapy and a final UVA radiation dose at clearance of 6.2 (+/- 2.5) J/cm2. The mean total dose of methotrexate was 93.0 mg (range, 67.5-127.5 mg). The only significant adverse effect seen was prolonged phototoxicity in eight patients. By reducing the total cumulative exposure dose of PUVA therapy, this treatment may reduce long-term side effects.