Estimation of benchmark dose for renal dysfunction in a cadmium non-polluted area in Japan

Previously, the association between urinary cadmium (Cd) concentration and indicators of renal dysfunction, including beta(2)-microglobulin (beta(2)-MG), total protein and N-acetyl-beta-D-glucosaminidase (NAG) were investigated in 1270 inhabitants > or = 50 years of age (547 men, 723 women) in a Cd non-polluted area in Japan and showed that a dose-response relationship existed between renal effects and Cd exposure in the general environment without any known Cd pollution. However, the threshold levels of urinary Cd could not be estimated at that time. In the present study, the threshold levels of urinary Cd were estimated as the benchmark dose low (BMDL) using the benchmark dose (BMD) approach. Urinary Cd excretion was divided into 6-7 categories, and an abnormality rate was calculated for each. Cut-off values for urinary substances were defined as corresponding to the 84% upper limit values, which were calculated from 2034 persons who had been living in the non-polluted areas and did not smoke. Then the BMD and BMDL were calculated using a log-logistic model. The values of BMD and BMDL for all urinary substances could be calculated. The BMDL for the 84% cut-off value of beta(2)-MG, setting an abnormal value at 5%, was 2.0 microg g(-1) creatinine (cr) in men and 1.6 microg g(-1) cr in women. In conclusion, the present study demonstrated that the threshold level of urinary Cd could be estimated in people living in the general environment without any known Cd-pollution in Japan, and the value was inferred to be almost the same as that in Belgium and Sweden.     

Benchmark dose approach for renal dysfunction in workers exposed to lead

Benchmark dose (BMD) and the lower confidence limit on the benchmark dose (BMDL) of blood lead were estimated to explore the biologic exposure limits for renal dysfunction caused by lead. One hundred thirty-five workers from one storage battery plant were selected as lead exposure group while 143 mechanics as the control. The relationship between the blood lead concentration and the urinary excretion of total protein (TP), beta2-microglobulin (beta2-MG), and N-acetyl-beta-D-glucosaminidase (NAG) was studied. The quantal linear logistic regression model (BMDS Version 1.3.1) was used to calculate BMD and BMDL of blood lead. The results showed that the levels of NAG, beta2-MG, and TP in lead-exposed workers were higher than those of control group and elevated along with rising length of employment. The levels of three indices for renal dysfunction increased with the elevated blood lead. The BMD and BMDL of blood lead for renal dysfunction were from 299.4 to 588.7 microg/L and from 253.4 to 402.3 microg/L, respectively. The BMDL of blood lead was ranged from high to low as TP, beta2-MG, and NAG. It is suggested that the urinary NAG activity could be a sensitive and early biomarker of renal tubular dysfunction induced by lead. When assessing renal function in workers occupationally exposed to lead, a blood lead level of 250 microg/L could serve as a warning signal.     

Estimation of benchmark dose for pancreatic damage in cadmium-exposed smelters.

The aim of this study was to estimate the benchmark dose (BMD) for pancreas dysfunction caused by cadmium (Cd) exposure in smelters. Smelter workers who had been exposed to Cd for more than 1 year and matching nonoccupationally exposed subjects were asked to participate in this study. Urinary cadmium (UCd) was used as a biomarker for exposure, serum insulin and amylase were used as biomarkers for pancreatic effects. In this study, serum insulin and amylase were lower in the smelter workers than in the nonoccupationally exposed subjects. A significant dose-response relationship with UCd was displayed. BMDs in terms of urinary Cd corrected for creatinine were calculated by use of BMDS (version 1.3.2). The benchmark dose lower limit of a one-sided 95% confidence interval (BMDL) for 10% excess risk was also determined. It was found that the BMDL10 for serum insulin and serum amylase was 3.7 and 5.3 microg/g Cr, respectively. Compared to the BMDL for renal damage caused by Cd exposure, identified by the effect biomarkers urinary beta2-microglobulin, urinary N-acetyl-beta-glucosaminidase, and urinary albumin (UALB), it was shown that BMDL10 for serum insulin is the lowest among all values and UALB gave the highest value (5.8 microg/g Cr). This study indicates that Cd exposure can result in pancreatic dysfunction and the effect appears at lower urinary Cd level than renal dysfunction. The endocrine function of the pancreas was affected at lower urinary levels of Cd, compared to the exocrine function, which was seen at higher urinary levels of Cd than those giving rise to renal tubular dysfunction.     

Bias induced by the use of creatinine-corrected values in evaluation of beta2-microgloblin levels

The present study was initiated to examine if the correction for creatinine (CR or cr) is the best approach among the three methods of correction for CR, correction for a specific gravity (SG or sg) and the use of observed values in managing difference in urine density. For this purpose, a database previously developed on 10,753 adult women in 10 non-polluted areas in Japan was re-visited for information on age, urinary levels of Cd, Mg, Ca, Zn, beta(2)-MG, and creatinine, and urine specific gravity as well as smoking habits. Never-smoking women with various urine density counted 8975 cases (the various urine density group). From these cases, 7081 cases with adequate urine density (i.e. 0.5 g/l < or = CR < or = 3.0 g/l and 1.010 < or = SG < or = 1.030) were selected (the adequate urine density group). When a beta(2)-MG level of 400 microg/g CR or 400 microg/l was taken as a cut-off value for beta(2)-MG-uria, both the prevalence of beta(2)-MG(cr)-uria [i.e. cases with beta(2)-MG (as corrected for CR) in excess of 400 microg/g cr] and that of beta(2)-MG(sg)-uria increased as a function of the decrease in Cd(cr) or Cd(sg). The prevalence of beta(2)-MG(ob)-uria also varied as a function of CR and SG, especially of CR, but its range of variation was smaller than the corresponding changes in beta(2)-MG(cr)-uria prevalence. A noteworthy advantage for the use of observed values over that of SG-corrected values was the minimum effect of age. In over-all evaluation, therefore, the recommended approach appeared to be the use of non-corrected observed values (after selection of urine samples for adequate urine density if desired) or correction for SG, rather than correction for CR.     

Threshold levels of urinary cadmium in relation to increases in urinary beta2-microglobulin among general Japanese populations

Through literature survey, paired data on cadmium (Cd) and beta(2)-microglobulin (beta(2)-MG) levels (as corrected for creatinine concentration) in urine (i.e., Cd-Ucr and beta(2)-MG-Ucr) among Japanese populations were available for 32 groups of men and 58 groups of women in 12 publications. Plotting of the Cd-Ucr and beta(2)-MG-Ucr data for the groups of women showed that beta(2)-MG-Ucr stayed unchanged when Cd-Ucr was at lower levels, whereas beta(2)-MG-Ucr increased sharply when Cd-Ucr was in excess of 10-20 microg/g cr. Regression analysis was made for groups of women with no elevation in beta(2)-MG-Ucr, and those with >400 or >1000 microg beta(2)-MG-U/g cr. A threshold Cd-Ucr level in relation to an increase in beta(2)-MG-Ucr was estimated as Cd-Ucr at the point of intercept of the two regression lines, one with no beta(2)-MG-Ucr elevation, and the other with >400 or >1000 microg beta(2)-MG-U/g cr. Cd-Ucr at the point of flexion thus calculated was 11-12 microg/g cr. Such observation was quantitatively reproduced by the analysis of data for men, giving 10-11 microg Cd-U/g cr at the point of flexion. This study suggests that the relationship of beta(2)-MG-Ucr with Cd-Ucr is not linear but in the shape of letter 'J', i.e., beta(2)-MG-Ucr increases sharply when Cd-Ucr is in excess of 10-12 microg/g cr.     

Recent applications of benchmark dose method for estimation of reference cadmium exposure for renal effects in man

The initial sign of cadmium (Cd)-induced renal effects is tubular damage, followed by glomerular damage. For the prevention of Cd-induced renal effects, it is essential to establish the reference exposure below which the risk of adverse health effects is low. In earlier Japanese studies, the estimated reference exposure of creatinine (cre)-adjusted urinary cadmium for renal tubular effect ranged from 1.6 to 4.0 μg/g cre in men and 2.3 to 4.6 μg/g cre in women. The benchmark dose (BMD) is defined as the exposure that corresponds to a certain response change from the background. The lower 95% confidence limit of the BMD (BMDL) can be used in risk assessment as a replacement for the no observed adverse effect level. This is a review of all relevant BMDL of Cd exposure for renal effects estimated so far. Based on studies in Japan, the best estimate is considered to be 1.5–3.2 μg/g cre for urinary Cd, 0.09–0.13 mg/kg for rice Cd concentration, and 0.9–1.4 g Cd for lifetime Cd intake. These BMDLs for renal effects were generally lower than the reference exposure expected from earlier studies, indicating the importance of further discussion regarding comprehensive measures to decrease the Cd exposure in the general population.     

Comparative evaluation of four urinary tubular dysfunction markers,with special references to the effects of aging and correction for creatinine concentration

Comparative evaluation was made on alpha(1)-microglobulin (alpha(1)-MG), beta(2)-microglobulin (beta(2)-MG), retinol binding protein (RBP) and N-acetyl-beta-D-glucosaminidase (NAG), as a marker of renal tubular dysfunction after environmental exposure to cadmium (Cd), with special references to the effects of aging and correction for creatinine concentration. For this purpose, a previously established database of 817 never-smoking Japanese women (at the ages of 20 to 74 years) on hematological [hemoglobin, serum ferritin (FE), etc.] and urinary parameters [alpha(1)-MG, beta(2)-MG, creatinine (cr), and a specific gravity] was revisited. For the present analysis, the database was supplemented by the data on RBP and NAG in urine. The exposure of the women to Cd was such that the geometric mean Cd in urine was 1.3 microg/g cr. Among the four tubular dysfunction markers, NAG showed the closest correlation with Cd, followed by alpha(1)-MG and then beta(2)-MG, and RBP was least so although the correlations were all statistically significant. The observed values of the markers gave the best results, whereas correction for a urine specific gravity gave poorer correlation, and it was the worst when correction for creatinine concentration was applied. Age was the most influential confounding factor. The effect of age appeared to be attributable at least in part to the fact that both creatinine and, to a lesser extent, the specific gravity decreased as a function of age. Iron deficiency anemia of sub-clinical degree as observed among the women did not affect any of the four tubular dysfunction markers. In conclusion, NAG and alpha(1)-MG, rather beta(2)-MG or RBP, are more sensitive to detect Cd-induced tubular dysfunction in mass screening. The use of uncorrected observed values of the markers rather than traditional creatinine-corrected values is recommended when comparison covers people of a wide range of ages.     

Threshold limit values of the cadmium concentration in rice in the development of itai‐itai disease using benchmark dose analysis

The aim of this study was to estimate the benchmark dose (BMD) as the threshold limit level of the cadmium (Cd) concentration in rice for itai‐itai disease and/or suspected disease; it was based on the data that previously evaluated the association for such diseases with the Cd concentration in rice by using a logistic regression model. From 1971 to 1976, a total of 2446 rice samples were analyzed across the 88 hamlets in the Jinzu river basin. The mean Cd concentration in rice in each hamlet was used as the index of external Cd exposure of the entire population of the hamlet. We employed the incidence of itai‐itai disease and/or suspected disease obtained from the available 55 hamlets. As the threshold, the lower limit of the BMD (BMDL) of the Cd concentration in rice for itai‐itai disease and/or suspected disease was estimated using a logistic model, setting the benchmark response at 1% or 2%. The estimated BMDLs of the Cd concentration in rice for itai‐itai disease and/or suspected disease were 0.62–0.76 and 0.27–0.56 mg kg⁻¹ in men and women, respectively. The lowest BMDL was 0.27 mg kg⁻¹ in women. In the present study, the threshold limit level of the Cd concentration in rice for itai‐itai disease, which is the most severe form of chronic Cd poisoning, was estimated for the first time. This result provides important information about the worldwide standard for the Cd concentration in rice. Copyright © 2017 John Wiley & Sons, Ltd.     

The reference dose for subchronic exposure of pigs to cadmium leading to early renal damage by benchmark dose method

Pigs were exposed to cadmium (Cd) (in the form of CdCl(2)) concentrations ranging from 0 to 32mg Cd/kg feed for 100 days. Urinary cadmium (U-Cd) and blood cadmium (B-Cd) levels were determined as indicators of Cd exposure. Urinary levels of β(2)-microglobulin (β(2)-MG), α(1)-microglobulin (α(1)-MG), N-acetyl-β-D-glucosaminidase (NAG), cadmium-metallothionein (Cd-MT), and retinol binding protein (RBP) were determined as biomarkers of tubular dysfunction. U-Cd concentrations were increased linearly with time and dose, whereas B-Cd reached two peaks at 40 days and 100 days in the group exposed to 32mg Cd/kg. Hyper-metallothionein-urinary (HyperMTuria) and hyper-N-acetyl-β-D-glucosaminidase-urinary (hyperNAGuria) emerged from 80 days onwards in the group exposed to 32mg Cd/kg feed, followed by hyper-β2-microglobulin-urinary (hyperβ2-MGuria) and hyper-retinol-binding-protein-urinary (hyperRBPuria) from 100 days onwards. The relationships between the Cd exposure dose and biomarkers of exposure (as well as the biomarkers of effect) were examined, and significant correlations were found between them (except for α(1)-MG). Dose-response relationships between Cd exposure dose and biomarkers of tubular dysfunction were studied. The critical concentration of Cd exposure dose was calculated by the benchmark dose (BMD) method. The BMD(10)/BMDL(10) was estimated to be 1.34/0.67, 1.21/0.88, 2.75/1.00, and 3.73/3.08mg Cd/kg feed based on urinary RBP, NAG, Cd-MT, and β(2)-MG, respectively. The calculated tolerable weekly intake of Cd for humans was 1.4 μg/kg body weight based on a safety factor of 100. This value is lower than the currently available values set by several different countries. This indicates a need for further studies on the effects of Cd and a re-evaluation of the human health risk assessment for the metal.     

Background exposure of general women populations in Japan to cadmium in the environment and possible health effects.

1. The surveys were conducted in 1990s on 470 non-smoking adult women [with no specific exposure to cadmium (Cd)] in 22 sites in six regions in Japan. 2. It was found that the dietary Cd intake (as a grand geometric mean) was 25.9 microg/day, the Cd level in blood was 2.1 microg/l, and Cd level in urine was 2.1 microg/g creat. 3. Cd in rice contributed about 30% of total dietary Cd intake. 4. There was a substantial reduction in Cd burden when compared with observation in 1980s. 5. Effects on kidney functions were essentially negative when evaluated in terms of beta2-microglobulin (beta2-MG), but might be positive when alpha1-microglobulin (alpha1-MG) was evaluated; further studies are apparently necessary. 6. No effects on liver functions were detected.     

Cadmium-induced renal dysfunction and mortality in two cohorts: disappearance of the association in a generation born later

The association between exposure to environmental cadmium and mortality was investigated in two cohorts. The study population consisted of 275 (cohort I) and 329 (cohort II) residents (aged >or=40 years) in a cadmium-polluted area, Nagasaki Prefecture, Japan, who had participated in health surveys conducted in 1982 and 1992, respectively. The follow-up period extended from 1982 or 1992 to 2005. In the study area, the dietary cadmium intake had decreased after 1980-1983 because of the restoration of cadmium-polluted paddy fields. In cohort I, the mortality rate among those with urinary beta2-microglobulin (beta2-MG) concentration >or=1000 microg/g creatinine (cr.) was 1.41 times higher than the regional reference rate (95% confidence interval [CI] 1.07-1.83). After adjusting for age and other variables, in men, urinary N-acetyl-beta-D-glucosaminidase, and in women, serum creatinine, beta2-MG clearance, and urinary beta2-MG were significantly associated with increased mortality. However, in cohort II, urinary beta2-MG or total protein was not significantly associated with survival. These findings indicate that cadmium-induced renal dysfunction was a significant predictor of mortality, but that such an association is disappearing, probably because of the selective loss of advanced cases and reduced exposure and body burden.     

Critical exposure level of cadmium for elevated urinary metallothionein--an occupational population study in China

Cadmium is a well-known nephrotoxic agent with extremely long biological half-time of 15-30 years in humans. To prevent nephrotoxicity induced by cadmium, it is necessary to identify specific and sensitive biomarkers of cadmium exposure and renal damage, and to define critical exposure levels related to minimal nephrotoxicity in humans. In this study, urinary cadmium (UCd) and blood cadmium (BCd) were used as cadmium exposure indicators, urinary beta(2)-microglobulin (UB2M), N-acetyl-beta-D-glucosaminidase (UNAG) and albumin (UALB) were applied as the effect biomarkers of tubular and glomerular dysfunction. The relationship between urinary metallothionein (UMT) and cadmium exposure biomarkers as well as effect biomarkers was examined. Significant correlations were found between the UMT and BCd, and UCd. At the same time, UB2M, UALB and UNAG showed positive correlation with UMT as well. According to this result, cadmium-exposed individuals with renal dysfunction excreted more metallothionein than those without. Dose-response relationships between UCd and urinary indicators of renal dysfunction were studied. The critical concentration of UCd was quantitatively estimated by the benchmark dose (BMD) method. The lower confidence limit of the BMD-10 (BMDL) of UCd (3.1 microg/g Cr) related to increased excretion of urinary metallothionein was slightly higher than that for UNAG (2.7 microg/g Cr), but lower than those of UB2M (3.4 microg/g Cr) and UALB (4.2 microg/g Cr). The results demonstrate that UMT may be used as a sensitive biomarker of renal tubular dysfunction in cadmium-exposed populations.     

Monitoring of cadmium toxicity in a Thai population with high-level environmental exposure

This study evaluated the utility of single and combined measurements of cadmium toxicity markers for surveillance purposes, using a sample of 224 individuals, 30-87 years of age, who were residents of cadmium polluted area in Mae Sot District, Tak Province, Thailand. Urinary cadmium levels excreted by them ranged between 1 and 58 microg/g creatinine with geometric mean of 8.2 microg/g creatinine which was 16-fold greater than the average for the general Thai population of 0.5 microg/g creatinine. The urinary markers evaluated were total protein, albumin, N-acetyl-beta-D-glucosaminidase (NAG), lysozyme, beta2-microglobulin (beta2-MG) and alpha1-microglobulin (alpha1-MG). Among these markers, only NAG showed a positive correlation with urinary cadmium in both male and female subjects with and without disease (r=0.43-0.71). Further, the prevalence rates for urinary NAG above 8 units/g creatinine (NAG-uria) increased with exposure levels in a dose dependent manner (p=0.05) among subjects with disease. In contrast, however, increased prevalence of beta2-MG above 0.4 mg/g creatinine (beta2-MG-uria) was associated with cadmium above 5 microg/g creatinine only in those without disease (POR=10.6 and 7.8 for 6-10 and >10 microg/g creatinine). Prevalence rates for abnormal excretion of all other markers, except albumin, were markedly increased among those having beta2-MG-uria with and without disease (chi2-test, p相似文献   

Urinary alpha 1-microglobulin as an indicator protein of renal tubular dysfunction caused by environmental cadmium exposure

An epidemiologic investigation was carried out to clarify the significance of the urinary excretion of alpha 1-microglobulin (alpha 1-MG) in people aged 50 years and over living in a Cd-polluted area in Japan. Approximately 80% of the population participated in the health examination. The urinary and serum levels and the relative clearance of alpha 1-MG to creatinine clearance were compared with various parameters (age, urinary beta 2-microglobulin (beta 2-MG), total protein, Cd, Cu and Zn, serum beta 2-MG, creatinine and blood urea nitrogen and relative clearances of alpha 1-MG, beta 2-MG, inorganic phosphate and uric acid). It was found that the urinary excretion of alpha 1-MG is closely associated with the urinary Cd and Cu and with the indices of renal dysfunction listed above. These results suggest that the urinary alpha 1-MG level markedly reflects a degree of proximal tubular dysfunction and that it may be useful as one of the screening measures for proximal tubular dysfunction caused by environmental Cd exposure.     

The relationships of urinary metallothionein with other indicators of renal dysfunction in people living in a cadmium-polluted area in Japan

An epidemiologic investigation was carried out to study the significance of urinary excretion of metallothionein (MT) in people aged 50 years and over living in a cadmium (Cd)-polluted area in Japan. The urinary level of MT was compared with various parameters (age, urinary alpha 1-microglobulin (alpha 1-MG), beta 2-microglobulin (beta 2-MG), total protein, Cd, copper (Cu), and zinc (Zn), and relative clearances to creatinine of alpha 1-MG, beta 2-MG, phosphate and uric acid). It was found that the urinary excretion of MT is closely associated with Cd and the indices of renal dysfunction listed above. This observation was more remarkable in women than men. When subjects with signs of renal dysfunction were compared as a group to those with normal renal functions, the excreted amount of MT in the former is significantly greater. The results support the notion that the urinary excretion of MT reflects not only Cd exposure levels but also renal dysfunction caused by long-term Cd exposure.     

alpha1-Microglobulin as a promising marker of cadmium-induced tubular dysfunction, possibly better than beta2-microglobulin

The purpose of the present study was to evaluate the validity of alpha1-microglobulin (alpha1-MG) in comparison with popularly used beta2-microglobulin (beta2-MG). A database on 8975 cases of never-smoking adult women was revisited; the data were based on spot urine samples from the women in 10 prefectures all over Japan. The validity of alpha1-MG was examined following essentially the same protocol as beta2-MG was examined in a previous study. Comparisons were made for alpha1-MG as observed (e.g. alpha1-MG(ob)), as corrected for creatinine (CR or cr) (e.g. alpha1-MGcr) and as corrected for a specific gravity (SG or sg) of 1.016 (e.g. alpha1-MGsg). A cut-off value of 5.0 mg alpha1-MG/g cr or l was deduced from 400 microg beta2-MG/g cr taking advantage of the regression equation between alpha1-MG and beta2-MG. The prevalence of alph1-microglobulinuria as corrected for a specific gravity of 1.016 (or alpha1-MGsg-uria in short) was essentially unchanged irrespective of SG, except for in very dense or very thin urine samples. alpha1-MGcr-uria prevalence decreased at higher CR. Comparison of the present observation with previous findings on beta2-MG-uria prevalence showed that the variation in prevalence of MG-uria as a function of urine density was smaller for alpha1-MGsg whereas it was substantially larger for beta2-MGcr, and thus it appeared prudent to consider alpha1-MGsg rather than beta2-MGcr as a marker of tubular dysfunction.     

Co-exposure to lead increases the renal response to low levels of cadmium in metallurgy workers

Purpose

Research on the effect of co-exposure to Cd and Pb on the kidney is scarce. The objective of the present study was to assess the effect of co-exposure to these metals on biomarkers of early renal effect.

Methods

Cd in blood (Cd-B), Cd in urine (Cd-U), Pb in blood (Pb-B) and urinary renal biomarkers, i.e., microalbumin (μ-Alb), beta-2-microglobulin (β₂-MG), retinol binding protein (RBP), N-acetyl-β-d-glucosaminidase (NAG), intestinal alkaline phosphatase (IAP) were measured in 122 metallurgic refinery workers examined in a cross-sectional survey.

Results and conclusions

The median Cd-B, Cd-U, Pb-B were: 0.8 μg/l (IQR = 0.5, 1.2), 0.5 μg/g creatinine (IQR = 0.3, 0.8) and 158.5 μg/l (IQR = 111.0, 219.3), respectively. The impact of Cd-B on the urinary excretion of NAG and IAP was only evident among workers with Pb-B concentrations ≥75th percentile. The association between Cd-U and the renal markers NAG and RBP was also evidenced when Pb-B ≥75th percentile. No statistically significant interaction terms were observed for the associations between Cd-B or Cd-U and the other renal markers under study (i.e., μ-Alb and β2-MG). Our findings indicate that Pb increases the impact of Cd exposure on early renal biomarkers.     

Evaluation of the benchmark dose method for dichotomous data: model dependence and model selection

The benchmark dose (BMD) method was evaluated using the USEPA BMD software. Dose-response data on cleft palate and hydronephrosis for a number of related polyhalogenated aromatic compounds were obtained from the literature. According to chi(2) test statistics, each dichotomous USEPA model failed to adequately describe only 1 of 12 cleft palate data sets. For hydronephrosis, the models were discriminated to a higher extent according to global goodness-of-fit. NOAELs for cleft palate corresponded to BMDLs (the approximate lower confidence limit on the BMD) for extra risks in the range of 5% or below. Model dependence of the BMDL estimate was more pronounced at lower levels of benchmark response (BMR). A BMR of 5% (extra risk) is recommended for cleft palate since model differences at this level were limited for all data. In addition, at BMRs of 5-10% the BMDL for all models was little affected by the specified confidence limit size (in the 90-99% range). For BMDL determination a conservative model selection approach was applied. At the suggested level of BMR (5%) this procedure resulted in use of the same model (multistage model) for the cleft palate endpoint in general. Akaike's information criterion (AIC) was considered for comparison between models. Determination of appropriateness of use of such methods in dose-response applications requires further analysis.     

Application of hybrid approach for estimating the benchmark dose of urinary cadmium for adverse renal effects in the general population of Japan

We used an updated hybrid approach to estimate the benchmark doses and their 95% lower confidence limits (BMDL) for cadmium‐induced renal effects in humans. Participants were 828 inhabitants (410 men, 418 women), aged 40–59 years who lived in three areas without any known environmental cadmium pollution. We measured urinary cadmium (U‐Cd) as a marker of exposure, and urinary protein, β2‐microglobulin (β2‐MG) and N‐acetyl‐β‐D‐glucosaminidase (NAG) as markers of renal effects. For urinary protein, the BMDL ranged from 0.9 to 1.1 µg g^?1 creatinine (cre) and approximately 1.6 µg per 24 h in men, and from 1.9 to 3.4 µg g^?1 cre and 2.0 µg per 24 h in women. For the renal tubular markers β2‐MG and NAG, the BMDL for U‐Cd ranged from 0.6 to 1.2 µg g^?1 cre and from 0.8 to 1.7 µg per 24 h in men, and from 0.6 to 2.3 µg g^?1 cre and from 0.6 to 2.1 µg per 24 h in women. The lowest BMDL for urinary cadmium (0.6 µg g^?1 cre) was somewhat lower than average urinary cadmium in Japanese older population. These results suggest the importance of measures to decrease cadmium exposure in the general population of Japan. Copyright © 2010 John Wiley & Sons, Ltd.     

An evaluation of benchmark dose methodology for non-cancer continuous-data health effects in animals due to exposures to dioxin (TCDD)

The U.S. Environmental Protection Agency (EPA) has conducted extensive reviews and analyses of health effects associated with exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Because the carcinogenicity of TCDD has received considerable attention from EPA and others, this paper focuses on animal data for non-cancer health effects that sometimes appear to be almost as sensitive as cancer to TCDD exposures. Benchmark dose (BMD) methodology can be used to identify point-of-departure (POD) estimates for use in derivation of reference doses or evaluation of margins of exposure. However, selection of an appropriate BMD methodology for assessment of non-cancer data, which are usually continuous (non-quantal), needs to be considered. One option available for a benchmark dose is to use a small percentage change in the mean response relative to the estimated maximum effect of TCDD at large doses. The benchmark based on a change estimated to equal 1% of the estimated maximum change from background to the asymptotic response at large doses (denoted as the relative ED01) was used by EPA in a reassessment of TCDD health risks. A lower confidence limit (LED01) could serve as a point of departure for setting a reference dose (RfD). This is a somewhat arbitrary effect level, generally within the background range of variation among unexposed animals, with an unknown risk. An alternative approach is recommended in which the risk of abnormal levels can be estimated. For continuous-data effects, a low and/or high percentile (e.g., 1st and/or 99th) in unexposed control animals can be used to define abnormal (not necessarily adverse) levels. From a dose-response curve and the standard deviation, it is possible to estimate the excess risk (proportion) of animals with abnormal levels as a function of dose for normally distributed levels. With this approach, the risk-based benchmark dose (BMD01) represents the dose with an estimated excess risk of 1% of the animals in the abnormal range rather than an arbitrary change in the value of the measured endpoint. Values for the relative and risk-based benchmark doses are computed from published data for a variety of non-cancer health effects associated with exposure to TCDD. For the 30 cases investigated, the BMD01 tended to vary around the lowest experimental dose tested, whereas the relative ED01 tended to be about a factor of three below the lowest dose, and the BMD01 was more precisely estimated than the ED01 as reflected by narrower confidence intervals. The BMDL01 values were on average more than fivefold higher than the corresponding LED01 values. However, these values still provide a conservative assessment for POD assessment, because the BMDL01 tends to be about an order of magnitude lower (more conservative) than the no-observed-adverse-effect level. This analysis demonstrates the potential impact of alternative choices in benchmark dose methodology. In combination with selection of appropriate adverse health effect endpoint(s) and studies, use of the risk-based BMD results in identification of more valid and meaningful POD estimates for non-cancer effects compared to the use of the relative ED approach.