Determination of biological exposure limit of damage in red blood cells caused by exposure to polycyclic aromatic hydrocarbons using benchmark dose method in general population / 公共卫生与预防医学

Objective To explore the biological exposure limit of blood system damage caused by long-term exposure to polycyclic aromatic hydrocarbons (PAHs) in non-occupational population by using the benchmark dose method, and to provide relevant reference for further improving the assessment of PAHs-induced health damage effects. Methods Adult residents living in downwind direction of a coke-oven plant in Shanxi Province were selected as the research subjects, and the information collected from baseline was used as the control. The metabolites of PAHs in urine were used as exposure biomarker, and the abnormal rate of red blood cell index was used as response biomarker. The relationship between urinary OH-PAHs and the erythrocyte damage rate was analyzed, and the benchmark dose (BMD) and the lower confidence limitation for the benchmark dose (BMDL) were calculated using Bayesian dose-optimizing software. Results The urinary PAH metabolites were mainly naphthalene and fluorene. The detection concentrations of 2-OHFlu and 1-OHPhe in the final year were higher than those in the baseline (P<0.05). With the increase of exposure years, the abnormal rate of red blood cells in the final year was higher than that in the baseline (P<0.05). In addition, the abnormal rate of red blood cells increased with the increase of the concentrations of five metabolites of PAHs in urine, and the chi-square trend test was significant (P<0.05). The benchmark dose (BMD) of OH-PAHs was 0.67 μmol/mol Cr, 0.82 μmol/mol Cr, 1.40 μmol/mol Cr and 0.78 μmol/mol Cr, respectively. The BMD of 2-OHNap in people with barbecue diet habits was 0.23 μmol/mol Cr. The BMD of 2-OHNap in people without barbecue diet habits was 1.44 μmol/mol Cr. Conclusion There is a dose-response relationship between the concentration of PAHs metabolites in urine and the damage of red blood cells. Long-term exposure to PAHs can lead to hematological damage. It is suggested that targeted public health interventions should be formulated to reduce the exposure of the general population to PAHs.

Benchmark Dose Assessment for Coke Oven Emissions-Induced Mitochondrial DNA Copy Number Damage Effects / 生物医学与环境科学（英文）

OBJECTIVE@#The study aimed to estimate the benchmark dose (BMD) of coke oven emissions (COEs) exposure based on mitochondrial damage with the mitochondrial DNA copy number (mtDNAcn) as a biomarker.@*METHODS@#A total of 782 subjects were recruited, including 238 controls and 544 exposed workers. The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction. Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95% confidence lower limit (BMDL).@*RESULTS@#The mtDNAcn of the exposure group was lower than that of the control group (0.60 ± 0.29 vs. 1.03 ± 0.31; P < 0.001). A dose-response relationship was shown between the mtDNAcn damage and COEs. Using the Benchmark Dose Software, the occupational exposure limits (OELs) for COEs exposure in males was 0.00190 mg/m 3. The OELs for COEs exposure using the BBMD were 0.00170 mg/m 3 for the total population, 0.00158 mg/m 3 for males, and 0.00174 mg/m 3 for females. In possible risk obtained from animal studies (PROAST), the OELs of the total population, males, and females were 0.00184, 0.00178, and 0.00192 mg/m 3, respectively.@*CONCLUSION@#Based on our conservative estimate, the BMDL of mitochondrial damage caused by COEs is 0.002 mg/m 3. This value will provide a benchmark for determining possible OELs.

Correlation analysis and benchmark dose study on bone metabolic biochemical index of low doses of exposed hydrogen fluoride workers / 中华劳动卫生职业病杂志

Objective: To analyze correlation of occupational hydrogen fluoride exposure to low doses of bone metabolism index through occupational epidemiological investigation and benchmark dose calculation. Methods: In May 2021, using cluster sampling method, 237 workers exposed to hydrogen fluoride in a company were selected as the contact group, and 83 workers not exposed to hydrogen fluoride in an electronics production company were selected as the control group. The external exposure dose and urinary fluoride concentration, blood and urine biochemical indicators of the workers was measured.The relationship between external dose and internal dose of hydrogen fluoride was analyzed. The external dose, urinary fluoride was used as exposure biomarkers, while serum osteocalcin (BGP), serum alkaline phosphatase (AKP) and urinary hydroxyproline (HYP) were used as effect biomarkers for bone metabolism of hydrogen fluoride exposure. The benchmark dose calculation software (BMDS1.3.2) was used to calculate benchmark dose (BMD) . Results: Urine fluoride concentration in the contact group was correlated with creatinine-adjusted urine fluoride concentration (r=0.69, P=0.001). There was no significant correlation between the external dose of hydrogen fluoride and urine fluoride in the contact group (r=0.03, P=0.132). The concentrations of urine fluoride in the contact group and the control group were (0.81±0.61) and (0.45±0.14) mg/L, respectively, and the difference between the two groups was statistically significant (t=5.01, P=0.025). Using BGP, AKP and HYP as effect indexes, the urinary BMDL-05 values were 1.28, 1.47 and 1.08 mg/L, respectively. Conclusion: Urinary fluoride can sensitively reflect the changes in the effect indexes of biochemical indexes of bone metabolism. BGP and HYP can be used as early sensitive effect indexes of occupational hydrogen fluoride exposure.

Benchmark dose estimation based on Bayesian model averaging and its application to evaluation of cadmium exposure of population in Baiyin / 环境与职业医学

Background The optimal model method for estimation of benchmark dose (BMD) does not consider the uncertainty of model selection. There is a lack of studies on using Bayesian model averaging (BMA) to estimate BMD. Objective To apply BMA to the exposure assessment of cadmium pollution in China, discuss the role of BMA in estimating BMD based on dose-response models, and to provide methodological support for health risk assessment of hazardous substances. Methods The parameters of five dose-response models (Gamma, Log-logistic, Log-probit, Two-stage, and Weibull models) estimated from the data from a cadmium-contaminated area in Baiyin City of Gansu Province and the urinary cadmium ranges in five cadmium-contaminated areas in China were used to simulate the data of varied correct models with different numbers of dosage groups (5 and 8) and different sample sizes (50, 100, and 200), then the performance of BMA and traditional optimal model were compared. The case analysis used the cadmium exposure data in Baiyin, Gansu Province. All analyses set urinary cadmium as the indicator of cadmium exposure, the abnormal rate of β2-microglobulin as the effect indicator, and the benchmark response to 10%. The correct model (the model used when simulating data), optimal model [the model with smallest Akaike information criterion (AIC)], and BMA were used to estimate BMD and lower confidence limit of benchmark dose (BMDL); the BMDs, BMDLs, and relative deviations from different methods were compared. Results In the simulation study, with increasing sample size or the number of dosage groups, the intervals of the 5th percentile and the 90th percentile of BMD tended to be narrower; when the correct model was a single model, the relative deviation of BMD estimation by BMA was greater than that of the traditional optimal model; when the correct model was an equal weight mixed model, the relative deviation of BMD estimation by BMA was less than that by the traditional optimal model. For the data of cadmium-contaminated areas, the optimal model was a Log-probit model (AIC=1814.46), followed by a Log-logistic model (AIC=1814.57); the BMDs (BMDLs) estimated by the Log-probit model, the Log-logistic model, and BMA were 3.46 (2.68), 3.16 (2.33), and 2.92 (2.07) μg·g−1, respectively. Conclusion The traditional optimal model is still recommended when the correct model is known. However, when the dose-response relationship of a hazardous substance is uncertain or with different sources or exposure grouping, compared with the traditional optimal model, BMA theoretically provides more stable estimation of BMD and BMDL by considering multiple possible alternative models.

A benchmark dose analysis for children urinary fluoride and it's correlation with the prevalence of dental fluorosis / 公共卫生与预防医学

Objective To investigate the situation of drinking water fluorosis in Tianjin, to study the benchmark dose of urinary fluoride, and to provide a reference for the formulation of the standard for urinary fluoride. Methods Three fluorosis endemic areas were selected in Tianjin, and three villages in each area were selected in this study. The water fluoride was detected, and the prevalence of dental fluorosis and the urinary fluoride of children aged 8-12 years old were investigated. Results The prevalence of dental fluorosis and urinary fluoride content in children in the villages with water fluoride exceeding the standard were significantly higher than those in the villages with water fluoride qualified, and the difference was statistically significant (χ2=88.821, P＜0.001; Z=6.089, P＜0.001). The analysis of the prevalence of dental fluorosis in children showed that the younger the age, the lower the prevalence and severity of dental fluorosis (χ2trend=14.584, P2trend= 20.525, P2=0.736, P=0.391; χ2=3.649, P=0.456). There were significant differences in urinary fluoride between children with different ages and genders (H=14.768, P=0.011; Z=-2.526, P=0.012). According to the level of urinary fluoride, the children were divided into 5 groups. With the increase of urinary fluoride concentration, the prevalence of dental fluorosis gradually increased and the difference was statistically significant (χ2trend=16.348, P<0.001), showing a dose-effect relationship. Based on the prevalence of dental fluorosis in children, BMDS was used to calculate the BMD and BMDL, which were 2.20 mg/L and 1.54 mg/L, respectively. Conclusion The water reform and fluoride reduction in Tianjin has achieved certain results. There is a dose-effect relationship between urinary fluoride and prevalence of dental fluorosis in children, and the reference dose value is slightly higher than the current standard, suggesting that the current standard can be updated timely.

Subchronic Oral Toxicity Evaluation of Sodium Dehydroacetate: A 90-day Repeated Dose Study in Rats / 生物医学与环境科学（英文）

Objective@#The present study was undertaken to evaluate the subchronic oral toxicity of sodium dehydroacetate (DHA-Na) and to determine the point of departure (POD), which is a critical factor in the establishment of an acceptable dietary intake.@*Methods@#DHA-Na was administered once daily by gavage to Sprague-Dawley rats at dose levels of 0.0, 31.0, 62.0, and 124.0 mg/kg BW per day for 90 days, followed by a recovery period of 4 weeks in the control and 124.0 mg/kg BW per day groups. The outcome parameters were mortality, clinical observations, body weights, food consumption, hematology and clinical biochemistry, endocrine hormone levels, and ophthalmic, urinary, and histopathologic indicators. The benchmark dose (BMD) approach was applied to estimate the POD.@*Results@#Significant decreases were found in the 62.0 and 124.0 mg/kg BW groups in terms of the body weight and food utilization rate, whereas a significant increase was found in the thyroid stimulating hormone levels of the 124.0 mg/kg BW group. Importantly, the 95% lower confidence limit on the BMD of 51.7 mg/kg BW was modeled for a reduction in body weight.@*Conclusion@#The repeated-dose study indicated the slight systemic toxicity of DHA-Na at certain levels (62.0 and 124.0 mg/kg BW) after a 90-day oral exposure.

Risk Assessment of Coumarin Intake in the Norwegian Population

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has at the request of the Norwegian Food Safety Authority (Mattilsynet) conducted a risk assessment of the coumarin intake in the Norwegian population. VKM was asked to assess if any part of the population has a total intake of coumarin that will exceed the tolerable daily intake (TDI). It should further be considered whether an intake of coumarin exceeding TDI 1-2 times a week for several years would represent a risk to the health of the consumer. The assessment has been performed by the VKM Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics (Panel 4). Coumarin is a naturally flavouring substance in cinnamon and occurs in many plants. The substance can be found in different types of cinnamon to a varying degree. The two main types are Ceylon (Cinnamomum zeylandicum) and Cassia cinnamon (Cinnamomum aromaticum). Cassia cinnamon, which currently is most frequently used in food products on the Norwegian market, contains more coumarin than the lesser used Ceylon cinnamon. Oral intake of coumarin is mostly related to consumption of cinnamon-containing foods or cinnamon as a spice. This includes both direct addition of cinnamon to foods as well as the use of cinnamon oils and other cinnamon extracts by the food industry. Other important sources of exposure could be food supplements based on cinnamon or the use of cosmetic products through dermal exposure, as synthetic coumarin is added as a fragrance ingredient to perfumes, skin gels, lotions and deodorants. It is known from animal experiments that coumarin can cause liver toxicity. It is considered as a non-genotoxic carcinogen in mice and rats. In 2004, the European Food Safety Authority (EFSA) established a TDI of 0.1 mg coumarin/kg body weight (bw), based on a no observed adverse effect level (NOAEL) for liver toxicity in a 2-year dog study. This TDI was maintained when the substance was re-evaluated in 2008. EFSA further concluded that exposure to coumarin resulting in an intake 3 times higher than the TDI for 1-2 weeks was not of safety concern. In order to answer the second question as stated in the terms of reference, the VKM Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics found it necessary to further examine the data on toxicity of coumarin, which were the basis for the TDI established by EFSA. The most significant hazards of coumarin appears to be liver toxicity, which is well documented, and demonstrated in mice, rats, dogs, baboons and humans, and kidney adenomas in male rats. In a review of human case reports, a small subgroup of the human population appears for unknown reasons to be more susceptible to medical treatment with coumarin. The lowest reported dose of coumarin associated with liver toxicity in humans is around 0.4 mg/kg bw/day. It should be noted that the liver toxicity of coumarin in humans usually is reversible. Since there were no dose-response data for humans, animal data were used in the hazard characterisation. The VKM Panel decided to use the benchmark dose (BMD) approach to determine a point of departure for adverse effects of coumarin. The 2-year chronic toxicity/carcinogenicity study in rats by the US National Toxicology Program (NTP) was chosen for model simulation and BMD/BMDL (benchmark dose lower confidence limit) calculations. The best model fit of the dose-response data combined with the lowest BMDL05 (dose where the response is likely to be smaller than 5%) was seen for increased relative liver weight in female rats, which gave a BMDL05 of 7 mg/kg bw/day (converted from 10 mg/kg bw, 5 times per week). The VKM Panel used the BMDL05 for relative increase in liver weight in female rats to establish a TDI of 0.07 mg/kg bw/day using an uncertainty factor of 100 to account for interand intraspecies variation. The intake calculations for coumarin from food and drinks in this opinion are based on both data from the nationally representative food consumption surveys Norkost, Ungkost, Småbarnskost and Spedkost, as well as on assumed worst intake scenarios of different cinnamon-containing food products. The average coumarin levels found in cinnamoncontaining food categories such as ginger bread, cinnamon buns and similar bakery products, cinnamon-containing cakes, thin pastry with cinnamon and cinnamon-based tea sold on the Norwegian market, were used to calculate the total coumarin intake in different age groups in the population. For the calculation of the coumarin intake from cinnamon powder sprinkled on oatmeal porridge and rice porridge, a coumarin level of 3000 mg/kg in cinnamon powder was used. The frequency of consumption and the amount of cinnamon powder (from ¼ - 1 teaspoon) sprinkled on the porridge were taken into account in the calculations. To assess if any part of the Norwegian population has an intake of coumarin that will exceed the TDI, the different intake scenarios presented in the opinion have been compared with the TDI of 0.07 mg/kg bw/day established by VKM. The main conclusions from the VKM Panel were: The total estimated intake of coumarin for mean and high consumers of cinnamon-containing foods are below the TDI for all age groups when consumption of cinnamon-based tea and porridge with cinnamon was excluded. Children and adults who regularly consume oatmeal porridge sprinkled with cinnamon may exceed the TDI by several folds depending on the frequency of consumption and the amount of cinnamon used. Small children (1- and 2-years old) who have a mean or high consumption of oatmeal porridge may exceed the TDI even if they use moderate amounts of cinnamon powder on the porridge. In a worst case scenario with high consumption of porridge and use of high amounts of cinnamon powder, the estimated coumarin intake could exceed the TDI by about 20-fold. This intake is similar to dose levels of coumarin used in medical treatment of adults and where cases of liver toxicity have been reported. Drinking of cinnamon-based tea, which may have a high content of coumarin, can also result in a total intake of coumarin that exceeds the TDI both for children and adults. Other relevant sources of coumarin are cosmetics and food supplements with cinnamon. The recommended dose of two cinnamon supplements sold on the Norwegian market can lead to an exceedance of TDI in adults. It is not anticipated that children will consume supplements with cinnamon. Cosmetic products (shower gels, body lotions, deodorants and oils) are important sources of coumarin exposure both for children and adults, but quantification of the coumarin exposure from cosmetics was not possible due to lack of data. The VKM Panel concludes that based on the available data, the possibility of an adverse health effect by exceeding the TDI 3-fold for 1-2 times per week for several years cannot be assessed. Generally, a minor or an occasional exceedance of TDI is not considered to increase the risk of adverse health effects. The coumarin intake could exceed the TDI by 7-20 fold in some instances. Liver toxicity may occur shortly after the start of coumarin exposure. Such large daily exceedances of TDI, even for a limited time period of 1-2 weeks, cause concern of adverse health effects.

Risk Assessment for Metalworking Fluids and Respiratory Outcomes

BACKGROUND: Metalworking fluids (MWFs) are mixtures with inhalation exposures as mists, dusts, and vapors, and dermal exposure in the dispersed and bulk liquid phase. A quantitative risk assessment was performed for exposure to MWF and respiratory disease.METHODS: Risks associated with MWF were derived from published studies and NIOSH Health Hazard Evaluations, and lifetime risks were calculated. The outcomes analyzed included adult onset asthma, hypersensitivity pneumonitis, pulmonary function impairment, and reported symptoms. Incidence rates were compiled or estimated, and annual proportional loss of respiratory capacity was derived from cross-sectional assessments.RESULTS: A strong healthy worker survivor effect was present. New-onset asthma and hypersensitivity pneumonitis, at 0.1 mg/m3 MWF under continuous outbreak conditions, had a lifetime risk of 45%; if the associated microbiological conditions occur with only 5% prevalence, then the lifetime risk would be about 3%. At 0.1 mg/m3, the estimate of excess lifetime risk of attributable pulmonary impairment was 0.25%, which may have been underestimated by a factor of 5 or more by a strong healthy worker survivor effect. The symptom prevalence associated with respiratory impairment at 0.1 mg/m3 MWF was estimated to be 5% (published studies) and 21% (Health Hazard Evaluations).CONCLUSION: Significant risks of impairment and chronic disease occurred at 0.1 mg/m3 for MWFs in use mostly before 2000. Evolving MWFs contain new ingredients with uncharacterized long-term hazards.

Avaliações toxicológicas das alterações genotóxicas e epigenóticas induzidas por Aroclor 1254 em testí­culo, espermatozóides, fí­gado e rim de camundongos / Toxicological assessments of genotoxic and epigenetic changes induced by Aroclor 1254 in testis, sperm, liver and kidney of mice

As bifenilas policloradas (PCBs) são um grupo de compostos hidrocarbonetos halogenados aromáticos, bioacumulativos em organismos vivos e persistente no ambiente. Além da atividade disruptora endócrina, os PCBs podem aumentar os níveis de espécies reativas de oxigênio (ROS), levando ao estresse oxidativo e alteração da metilação de DNA que são fatores importantes nas etiologias da hepatotoxicidade, infertilidade masculina e doença renal. Estes agentes tóxicos podem causar disfunção mitocondrial e distúrbios que afetam a produção de ATP, ROS e morte celular, ocasionando danos à saúde humana. O presente trabalho tem como objetivo investigar possíveis alterações genotóxicas e epigenéticas causadas pelo aroclor 1254 em fígado, rim e testículo, além de verificar a indução de estresse oxidativo e disrupção dos metabólitos intermediários do ciclo de Krebs nos referidos tecidos. Camundongos machos C57/BL6 foram expostos ao Aroclor 1254 em diferentes doses (5, 50, 500 e 1000 ug/kg) por gavagem, uma vez a cada três dias, durante 50 dias. Após a exposição, os animais foram eutanasiados, os órgãos coletados e espermatozoides obtidos a partir dos epidídimos. A peroxidação lipídica em plasma e tecidos foi avaliada pela quantificação de malonaldeído (MDA) por HPLC/DAD. Os níveis de intermediários da via glicolítica, do ciclo de Krebs, de alguns nucleotídeos e aminoácidos, marcas epigenéticas (5-mC e 5-hmC) e adutos de DNA (8-oxodG e CEdG) foram quantificados por HPLC-ESI-MS/MS. A abordagem de benchmark dose (BMD) foi utilizada para a modelagem dose resposta. Após exposição, não foram observadas diferenças significativas da variação da massa corporal, e a razão do peso testicular, fígado e rim por massa corporal. No tecido hepático, foi observado aumento da peroxidação lipídica. Houve redução significativa dos níveis de ATP, ADP, razão NADP+/NADPH, piruvato, malato, fumarato e glutamato. Observou-se redução significativa dos níveis de 5-mC e 5-hmC no DNA nuclear (nDNA), enquanto não foram observadas alterações dos níveis dos adutos. Em DNA mitocondrial (mtDNA) não foram observadas alterações nas marcas epigenéticas, no entanto foi obtido aumento significativo no aduto 8-oxodG após exposição ao Aroclor 1254. No tecido renal foi observado aumento significativo de MDA. Houve aumento significativo dos níveis de lactato e malato e reduções de ATP, ADP, glutamina, NAD+. Foi observada a hipohidroximetilação do mtDNA. As marcas 5-mC de mtDNA, 5mC de nDNA e adutos de DNA nuclear e mitocondrial não apresentaram diferenças após exposição a PCBs. Nos testículos foi verificada redução significativa dos níveis de glutamato, malato, succinato, fumarato e razão NADH/NAD+, hipohidroximetilção em mtDNA e hipermetilação em nDNA. Não foram observadas alterações de 5-mC em mtDNA e 5hmC em nDNA. Não foram verificadas alterações dos níveis de MDA e adutos em nDNA. Adicionando, foi observada redução dos níveis de 5-mC em DNA global de espermatozoide. Os limites inferiores do intervalo de confiança da BMD foram estimados para que estes marcadores possam ser usados na avaliação de riscos de PCBs. Os dados obtidos apontam o Aroclor 1254 como indutor de alterações do metabolismo intermediário, das marcas epigenéticas e estresse oxidativo. Essas alterações podem afetar vias celulares, levando à morte ou transformação, e aumentando o risco de doenças

Polychlorinated biphenyls (PCBs) are a group of aromatic halogenated hydrocarbon compounds, which bioaccumulate in living organisms and is persistent in the environment. Besides their endocrine disrupting activity, PCBs may increase the levels of reactive oxygen species (ROS), leading to oxidative stress and alter DNA methylation that are important factors in the etiology of liver toxicity, male infertility, and kidney disease. These toxic agents can cause mitochondrial dysfunction and disorders that affect the production of ATP, ROS and cell death, thereby leading to health-related problems. The present work aimed at investigating possible genotoxic and epigenetic changes caused by aroclor 1254 in the liver, kidney and testis, as well as determine the induction of oxidative stress and disruption of intermediate metabolites in these tissues. Male C57/BL6 mice were exposed to Aroclor 1254 at different doses (5, 50, 500 and 1000 µg/kg) by gavage, once every three days, for 50 days. After the exposure period, the animals were euthanized, organs collected, and sperms obtained from the epididymis. Lipid peroxidation in plasma and tissues was determined by quantification of malonaldehyde (MDA) using HPLC/DAD. The levels of intermediate metabolites, epigenetic marks (5-mC and 5-hmC) and DNA adducts (8-oxodG and CEdG) were quantified by HPLC-ESI-MS/MS. The Benchmark dose approach (BMD) was used for dose response modeling. No significant differences in body weight variation, testicular, liver and kidney weight to body weight ratio were observed after exposure. However, in hepatic tissues, an increase in lipid peroxidation was observed. There were significant decreases in the intermediate metabolites including the levels of ATP, ADP, pyruvate, NADP+/NADPH ratio, malate and fumarate, as well as glutamate. Significant reduction of 5-mC and 5-hmC levels in nuclear DNA (nDNA) were observed, whereas no changes were observed in DNA adducts. The epigenetic marks in mitochondrial DNA (mtDNA) were not changed; however, a significant increase was observed in 8-oxodG adduct after exposure to Aroclor 1254. In renal tissues, data showed a significant increase in MDA, while for the intermediate metabolites, the levels of lactate and malate were significantly elevated, whereas significant reductions were recorded for ATP, ADP, glutamine, and NAD+. Hypohydroxymethylation was observed in mtDNA. The 5-mC of mtDNA, 5mC of nDNA and nuclear and mtDNA adducts did not show differences after PCBs exposure. For the testicles, significant reductions in the levels of glutamate, malate, succinate, fumarate and NADH/NAD+ ratio were observed. The PCBs also induced hypohydroxymethylation in mtDNA and hypermethylation in nDNA, but there were no changes of 5-mC in mtDNA and 5-hmC in nDNA. A reduction of nDNA adducts 8-oxodG was observed. No changes were observed in the level of MDA and DNA adducts of nDNA. However, after PCBs exposure there was a significant decrease of 5-mC in global DNA of spermatozoa. The lower bound confidence interval on BMD, which were estimated for these markers can be used in the risk assessment of PCBs. Collectively, the data obtained in this study indicate that Aroclor 1254 induces alteration of intermediate metabolites, epigenetic marks and oxidative stress. These changes can adversely affect cells and cellular pathways, therefore increase the risk of cell death or transformation

Subchronic Oral Toxicity Evaluation of Lanthanum: A 90-day, Repeated Dose Study in Rats / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>The present study was undertaken to evaluate the subchronic toxicity of lanthanum and to determine the no observed adverse effect level (NOAEL), which is a critical factor in the establishment of an acceptable dietary intake (ADI).</p><p><b>METHODS</b>In accordance with the Organization for Economic Co-operation and Development (OECD) testing guidelines, lanthanum nitrate was administered once daily by gavage to Sprague-Dawley (SD) rats at dose levels of 0, 1.5, 6.0, 24.0, and 144.0 mg/kg body weight (BW) per day for 90 days, followed by a recovery period of 4 weeks in the 144.0 mg/kg BW per day and normal control groups. Outcome parameters were mortality, clinical symptoms, body and organ weights, serum chemistry, and food consumption, as well as ophthalmic, urinary, hematologic, and histopathologic indicators. The benchmark dose (BMD) approach was applied to estimate a point of departure for the hazard risk assessment of lanthanum.</p><p><b>RESULTS</b>Significant decreases were found in the 144.0 mg/kg BW group in the growth index, including body weight, organ weights, and food consumption. This study suggests that the NOAEL of lanthanum nitrate is 24.0 mg/kg BW per day. Importantly, the 95% lower confidence value of the benchmark dose (BMDL) was estimated as 9.4 mg/kg BW per day in females and 19.3 mg/kg BW per day in males.</p><p><b>CONCLUSION</b>The present subchronic oral exposure toxicity study may provide scientific data for the risk assessment of lanthanum and other rare earth elements (REEs).</p>

Sub-chronic toxicity of MNT-016 by benchmark dose method in Sprague-Dawley rats / 军事医学

Objective To evaluate the repeated dose toxicity of MNT-016 in SD rats and to provide reference for toxicity evaluation.Methods MNT-016 was administered to rats at 5, 20 and 80 mg/kg for 90 days.The toxic effects on the animals were evaluated by observing the clinical signs and measuring the body weight, hematology and blood biochemistry as well as histopathological examination.NOAEL and benchmark dose lower confidence limit(BMDL) were observed by the end point of toxicity.Results Compared with the control group, the AST, TBIL, DBIL and Crea of male rats were increased in a dose-dependent manner, while TG and CHOL decreased.The body mass(before anatomy), heart, liver, thymus, epididymis of male rats in 80 mg/kg group were significantly decreased (P<0.05), while absolute organ mass of the heart and lung was increased.The body mass (before anatomy) and thymus of female rats in 80 mg/kg group were significantly decreased (P<0.05), while absolute organ mass of lungs was increased.Vacuolation of hepatocytes was observed in groups each dose, tubule atrophy was found in the kidneys of 20 and 5 mg/kg groups, and tubule basophilia was observed in 80 mg/kg group.The incidence of the above lesions was higher in male animals than in female ones.Conclusion The NOAEL of MNT-016 is lower than 5 mg/kg in male rats and 5 mg/kg in female rats.BMDL value is 2.65 mg/kg in male animals and more accurate than NOAEL, and is 9.04 mg/kg in female animals,which is slightly larger than the corresponding NOAEL.

The Study and Application of Nonparametric Bayesian Methods for Benchmark Dose Estimation / 中国卫生统计

Objective Comparing the performance of the two nonparametric Bayesian methods for benchmark dose estimating under different dose response data,then comparing them with traditional parametric methods.Methods Introduce the basic principle of the nonparametric Bayesian method based on weighted process and stochastic process separately,then compared the estimations through simulate study and instance analysis.Results The simulate study shows that the posterior estimates were reasonably close to the target true BMD value for the two nonparametric methods,and NBP2 is more desirable compared to NPB1.The nine examples indicate that the BMD estimates from the nonparametric approaches generally fall into or very near the interval of those obtained from BMDS and nonparametric approaches tend to produce lower BMDLs than the parametric modeling approaches.Conclusion The posterior estimates were reasonably close to the target true BMD value for the two nonparametric methods,especially when standard parametric models fail to fit to the data adequately.The NPB2 method is slightly bet-ter than the NPB1 method in the aspect of estimation result and the software operation speed.

Benchmark dose of saliva fluoride concentration in adolescents and it's relationship to the prevalence of dental fluorosis / 中华地方病学杂志

Objective To study the benchmark dose (BMD) of fluoride concentration in saliva,and to evaluate the significance of saliva fluoride on control and prevention of endemic fluorosis.Methods In September 2014,middle school students in endemic fluorosis areas and non-endemic fluorosis areas in North China Petoleum were selected as objects.The contents of fluoride in water,urine and saliva were determined.The correlation of fluoride content in water,urine fluoride and fluoride concentration in saliva was analyzed.According to the levels of the saliva fluoride concentration,the children were divided into 11 groups,＜ 1.00,1.00-,2.00-,3.00-,4.00-,5.00-,6.00-,7.00-,8.00-,9.00-and ≥ 10.00 mg/L.The prevalence of dental fluorosis and defected dental fluorosis were investigated and the saliva fluoride concentration was calculated by Banch-Mark Dose Software.Results Compared with non endemic areas,the fluoride contents in water,urine and saliva [(2.13 ± 0.13),(1.29 ±0.73),(4.01 ± 3.61) mg/L] were higher than that in endemic areas [(0.67 ± 0.13),(0.38 ± 0.08),(0.75 ± 0.12) mg/L,t =158.730,24.780,18.114,all P ＜ 0.01].The fluoride concentration in saliva was positively correlated with the fluoride content in water and urine in endemic areas (r =0.626,0.945,all P ＜ 0.01).The (BMDs and benchmark dose lower bound (BMDLs) were 0.91,0.54,3.72,3.32 mg/L respectively,calculated by Banch-Mark Dose Software.With the increase of fluoride concentration in saliva,the prevalence of dental fluorosis and defect dental fluorosis had increased too,especially when the fluoride content in saliva was more than 4 mg/L.There were significant doseresponse relationships between the urine fluoride and the prevalence of dental fluorosis and defected dental fluorosis.Conclusion The fluoride concentration in saliva could be used as one of the evaluation indexes of fluorosis,and the BMD of saliva fluoride concentration in endemic fluorosis areas is suggested as 0.91 mg/L.

Research progress in benchmark dose in risk assessment of long-team exposure toxicity / 军事医学

The purpose of risk assessment is to evaluate the permissible exposure level under specific risk factors.To extrapolate the human acceptable daily intake (ADI) and/or reference dose (RfD), the traditional method uses the no-observed-adverse-effect level ( NOAEL ) to quantify toxicity after being divided by uncertainty factor.There are many limitations with NOAEL method in safety evaluation,for it relies too much on experimental design.Benchmark dose ( BMD) approach is a more reliable method with many advantages.BMD approach and its analysis software, the advantages of BMD over NOAEL, the application and methodological perfection in risk assessment of long-team exposure toxicity are presented in this review.

Biological exposure limit in bone metabolism damage induced by co-exposure to fluorine and arsenic from coal burning / 中国地方病学杂志

Objective To study the biological exposure limit in bone metabolism damage caused by coexposure to fluorine and arsenic from coal burning in exposed population.Methods One hundred and ninety-eight cases of fluoride and arsenic co-exposed people from Liuchang village,Qinzhen city,Guizhou province were enrolled in the study.Urinary fluorine (UF),urinary arsenic (UAs),urinary hydroxyproline (UHYP),ross-linked Ntelopeptides of type Ⅰ collagen(UNTX) and bone strength index(STI) were detected.BMDS Version 2.1 software was used to calculate UF,UAs benchmark dose (BMD) and its lower confidence limit (BMDL) on the damage of bone metabolism caused by co-exposure to fluorine and arsenic from coal burning.Results The BMD and BMDL range of UF caused by co-exposure to fluorine and arsenic from coal burning were 0.68-1.35 mg/g Cr,0.57-1.11 mg/g Cr.The BMD and BMDL range of UAs caused by co-exposure to fluorine and arsenic from coal burning were 8.36-18.77 μg/g Cr,7.12-15.40 μg/g Cr.Conclusion The biological exposure limits of UF and UAs for bone metabolism toxicity are proposed as 0.57 mg/g Cr and 7.12 μg/g Cr in co-exposure to fluoride and arsenic from coal burning,respectively.

Application of benchmark dose on the study of people's liver dysfunction induced by arsenic-coal burning and its significance / 中国地方病学杂志

Objective To explore the biological exposure limit of liver dysfunction induced by arsenic-coal burning, and screen sensitive biornarkers for its' liver dysfunction monitoring. Methods One hundred and eighteen subjects from the exposed area and 50 control from non-pollution area were studied. Their urinary and hair contents of arsenic were tested as exposure biomarkers by Ag-DDC assay. Total bile acid(TBA, detected by enzymatic cycling method), glutathione S-transferase (GSTs, detected by chemical colorimetry) and γ-glutamyl transpeptidase (γ-GT, detected by colorimetry of diazotization reagent) were used as biomarkers indicating liver cell damage. were used as liver fibrosis biomarkers. The benchmark dose (BMD) and the lower confidence limit of benchmark dose(BMDL) of urinary and hair arsenic were calculated. Sensitivity of each biomarker was estimated according to the BMD and BMDL value. Results The geometric mean of urinary and hair arsenic(98.50 mg/kg Cr, 7.42 mg/kg) μg/L) in the exposed group were significantly higher than urinary and hair arsenic (22.98 mg/kg Cr, 1.28 mg/kg) and each biomarker in the control group(4.63 μmol/L, 13.76 U/L,36.45 U/L,54.62 μg/L,74.45 μg/L,54.81 μg/L, P<0.01). Significant dose-effect relationship existed between urinary and hair arsenic contents and each biomarker. BMD and BMDL value of urinary arsenic was 49.53-101.96 mg/kg Cr and 39.02-70.15 mg/kg Cr, respectively. Those of hair arsenic were 3.04-5.02 mg/kg and 2.36-3.25 mg/kg, respectively. According to BMD and BMDL value of urinary and hair arsenic, the sensitivity of biomarkers decreased in the order of GSTs, TBA and Conclusions According to the lowest BMD and BMDL of urinary and hair arsenic, averaged reference value of urinary and hair arsenic in the local normal population, we suggest urinary 35.0 mg/kg Cr and hair 2.5 mg/kg as their biological exposure limits for those with liver dysfunction induced by arsenic-coal burning. GSTs, TBA, γ-GT and HA, Ⅳ. C, PC-Ⅲ can respectively reflect liver cell damage and liver fibrosis caused by arsenic-coal burning in different degrees, among which, GSTs and HA are the most sensitive biomarkers respectively for liver cell damage and liver fibrosis.