FOR Simon ET AL - ars.els-cdn.com€¦ · Web viewThe relationship between exposure concentration and steady state blood concentration in humans is linear as shown in Figure S1

Simon et al. Supplementary Content Bayesian Methods for Uncertainty Factors

Supplementary Content: Individual Chemical Assessments used in Simon et al. “Bayesian Methods for Uncertainty

Factor Application for Derivation of Reference Doses”

SUPPLEMENTARY CONTENT: BAYESIAN METHODS FOR UNCERTAINTY FACTOR APPLICATION FOR DERIVATION OF REFERENCE DOSES

1


This supplement provides details of the assessments and calculations for the twenty-four IRIS values considered here. Necessarily, details of each evaluation will be slightly different but will generally follow the methods and approaches described in the body of the report. Here, the approach used by the IRIS program, the combination of the composite UF with the uncertainty in the POD, and the combination of individual UFs and the uncertainty in the POD are described.

1 Reference Concentration for AmmoniaThe POD for ammonia is based on a NOAEL from Holness et al. (1989). This study examined workers in a soda ash plant with chronic exposure to ammonia. Exposures were based on personal sampling. Four exposure groups were designated: 0.2 mg/m3, <4.4 mg/m3, 4.4 – 8.8 mg/m3 and 8.8 – 17.7 mg/m3. No exposure-related differences were observed in measures of lung function, subjective effects or sense of smell. There were 12 workers in the high exposure group and 3 were exposed to concentrations up to 17.7 mg/m3.

From Rahman et al. (2007), which examined ammonia and urea plant workers, EPA selected a NOAEL of 4.9 mg/m3 and a LOAEL of 18.5 mg/m3 based on respiratory symptoms and decrease in lung function. There were 24 workers in the NOAEL group and 64 in the LOAEL group.

The LOAEL from Rahman et al. (2007) supports the NOAEL range identified by EPA from Holness et al. (1989). However, a higher and possibly more appropriate NOAEL value might have been selected from the range of 8.8 to 17.7 mg/m3, possibly a measure of the midpoint of this range.

Since the RfC is based on human studies, the overall UF was 10, accounting only for human variability or UFH.

1.1 Ammonia RfC: Approach 1—the IRIS DerivationThe NOAEL value of 8.8 mg/m3 was duration- and activity-adjusted as described on p. 2-5 of the Ammonia Toxicological Review to obtain a value of 3.1 mg/m3. The calculation is shown below

The midpoint of the NOAEL range is 13.25 mg/m3. Had this value been used, the RfD would be 0.5 mg/m3.


2


1.2 Ammonia RfC: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

Using the duration- and activity-adjusted NOAEL value of 3.1 mg/m3, the overall UF can be applied as follows:

Hence, for the ammonia RfC, there is no difference in the RfD with application of UFs as Bayesian priors.

1.3 Ammonia RfC: Approach 3—Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

This approach is not application to the ammonia RfC because a single UF was applied and no PBPK model or DAF was used. Hence, the value would be the same at that in the IRIS derivation. Although WHO-IPCS (2014) provides distributions for the uncertainty in a NOAEL, none are applicable to inhalation.


3


2 Reference Dose for n-ButanolThe RfD for n-butanol was derived from developmental effects observed in rats by Sitarek et al. (1994). BMD analysis was used based on a BMR of 10% extra risk in terms of affected litters. The log-logistic model provided a BMD10 of 56.5 mg/kg/d and a BMDL10 of 26.1 mg/kg-d. The composite UF was 300 consisting of UFA = 10, UFH = 10 and UFD = 3.

2.1 n-Butanol RfD: Approach 1—the IRIS DerivationThe composite UF of 300 was applied directly to the BMDL as follows:

2.2 n-Butanol: RfD: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution

The standard deviation of the normal distribution of the BMD on a natural log scale is

The standard deviation of the composite UF in log space is 3.468. These two values were combined as follows:

Applying this uncertainty to ln(BMD) by subtraction gives

The resulting RfD is the antilog or 0.178 rounded to 0.2 mg/kg-d. This RfD value is over two fold greater than that derived by EPA.

2.3 n-Butanol RfD: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

Using the default values of the three UFs at the 95th percentile, the RfD is calculated as


4


The RfD would be 2 mg/kg-d, more than twenty-fold higher than the IRIS RfD value.

3 Reference Concentration for n-ButanolImpaired neuromuscular function observed by Korsak et al. (1994) was chosen by EPA as the critical effect. A LOAEL of 308 mg/m3 and a NOAEL of 154 mg/m3 were identified. The area-under-the-curve (AUC) concentration in arterial blood was selected as the dose metric for PBPK modeling to address animal-to-human toxicokinetic extrapolation. The AUC corresponding to the NOAEL was 0.01281 mM. A composite UF of 1000 was used consisting of UFA = 3, UFH = 10, UFD = 3 and UFS = 10.

3.1 n-Butanol RfC: Approach 1—the IRIS DerivationThe animal NOAEL of 154 mg/m3 corresponded to the 24-hour average AUC in arterial blood of 0.01282 mM. To achieve the same AUC in humans, the HEC would be 59 mg/m3, derived from a PBPK model. To the NOAEL-HEC, the composite UF of 1000, consisting of UFA = 3, UFH = 10, UFD = 3 and UFS = 10, was applied to obtain an RfC of 0.06 mg/m3.

3.2 n-Butanol: RfC: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution

The standard deviation of the composite UF in log space corresponding to 95% one-sided confidence limit or two-sided 90% CI is 4.200. This value was applied to the NOAELHEC as follows:

The antilog of this result or 0.059 mg/m3 and rounded to 0.06 mg/m3 is the same as the IRIS value.

3.3 n-Butanol RfC: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

The PBPK model used by EPA was a modification of the one developed by Teeguarden et al. (2005)Teeguarden et al., (2005). Although EPA provided the code for the model, the implementation of the model was beyond the scope of this report. Instead, Teeguarden et al. (2005) provided response surface information for both humans and rats


5


as steady state arterial blood concentrations corresponding to a range of exposure concentrations. The relationship between exposure concentration and steady state blood concentration in humans is linear as shown in Figure S1 below.

Because EPA altered the model from that of Teeguarden et al. (2005), the plots supported the assumption that these relationships were linear and went through the origin. The multipliers were derived from the values provided in the n-butanol Toxicological Review (USEPA, 2011a). The rat NOAEL of 154 mg/m3 was equivalent to 0.01282 mM AUC. The multiplier would be 12012.5 The multiplier for corresponding to conversion of the human AUC to an external dose is 59/0.01282 = 4602.

To the rat NOAEL of 154 mg/m3, UFS = 10 is applied to obtain the estimate of the chronic NOAEL. The Bayesian calculation is:

The antilog of this value is 15.4 mg/m3, representing the chronic NOAEC. Because of the linear relationship between exposure and steady state blood concentration, the corresponding AUC is

To this dose metric is applied UFA = 3, representing the toxicodynamic component of interspecies uncertainty.

The antilog of this value is 0.0004272 mM, the human AUC and the corresponding exposure is 1.97 mg/m3.

UFD and UFH are combined and applied as follows:


6

Figure S1. Plot of 24-hr average blood concentration in humans vs. exposure concentration in mg/m3, showing the linearity of the relationship. The relationship is also linear in rats.


The antilog of this value is 0.154 mg/m3 rounded to 0.2 mg/m3 would be over three-fold higher than the EPA value.


7


4 Reference Dose for Vanadium PentoxideEPA identified a decrease in RBC count in rats as the critical effect (Mountain et al., 1953). A LOAEL was identified at 16.4 mg/kg-d and a NOAEL at 10.5 mg/kd-d. Interspecies extrapolation was conducted in part by the use of a DAF based on allometric scaling. The value of the DAF was 0.244. The composite UF was 3000, consisting of UFA = 3, UFH = 10, UFS = 10, and UFD = 10.

4.1 Vanadium Pentoxide RfD: Approach 1—the IRIS DerivationThe NOAEL was converted to a HED using the DAF as follows:

To this value was applied the composite UF to obtain a value of 9E-04 mg/kg-d.

4.2 Vanadium Pentoxide RfD: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution

To the HED, the composite UFs was applied in a Bayesian framework as follows:

Here the value of 4.8675 represents the standard deviation of the underlying lognormal distribution for a composite UF of 3000 at the 95th percentile. This value is not presented in the Table 7.2 in NRC (2014).

The value of the RfD is the antilog of -7.042 equal to 9E-04 mg/kg-d, the same as that in the IRIS derivation.

4.3 Vanadium Pentoxide RfD: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

UFS was applied to the animal NOAEL as follows:

ln(10.5) – 1.645*1.4 = 0.0484 The DAF was applied to the antilog of this value.

1.05 mg/kg/d * 0.244 = 0.256 mg/kg/d UFA, UFH and UFD were applied as follows:


8


The antilog of this value would be 0.0082 or 8E-3 mg/kg/d, almost ten fold higher than the value in IRIS.


9


5 Reference Concentration for Vanadium PentoxideChronic inflammation of the larynx in female rats was chosen as the critical effect (National Toxicology Program, 2002). The rats were exposed for 6 hours per day and 5 days per week. Based on USEPA (1994), the regional deposited dose ratio (RDDR) for the extrathoracic region was used a part of the species extrapolation. The HECs were calculated using adjustment for continuous exposure and the RDDR. The reported concentrations were 0, 0.5, 1 and 2 mg/m3 and the corresponding HECs were 0, 0.02, 0.05 and 0.09 mg/m3. BMD evaluation was conducted on the HECs using a 10% POD. The BMD10 value was 0.00454 mg/m3 and the BMDL10 value was 0.00313 mg/m3. The composite UF was 300, consisting of UFA = 3, UFH = 10, and UFD = 10.

5.1 Vanadium Pentoxide RfC: Approach 1—the IRIS DerivationThe composite UF of 300 was applied to the BMDL10 value of 0.003 mg/m3 to obtain an RfC of 1E-05 mg/m3.

5.2 Vanadium Pentoxide RfC: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution

The uncertainty associated with BMD modeling is calculated as:

This uncertainty was combined with the composite UF in a Bayesian Framework and applied to the POD by subtraction:

The antilog of this result is 1.5E-05 mg/m3 and would round to 2E-05 mg/m3, twice the IRIS value.

5.3 Vanadium Pentoxide RfC: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

The calculation is performed as follows:


10


The antilog of this result is 1.43E-04 mg/m3, which would round to an RfC value of 1E-04 mg/m3, an order of magnitude higher than the IRIS value.

6 Reference Concentration for MethanolDecrements in brain weight in rats at six weeks of age from exposure during the gestational and postnatal periods was chosen as the critical effect. External doses in units of ppm were converted to an internal dose metric with a rat PBPK model. The internal dose metric was AUC in blood adjusted for background in units of mg-hr/L. The BMD-1SD was 1730.35 mg-hr/L and the BMDL-1SD was 858.04 mg-hr/L. The composite UF was 100, consisting of UFA = 3, UFH = 10 and UFD = 3.

In contrast to other assessments, the composite UF was applied to the dose metric and subsequently, the human PBPK model was used to obtain the RfC. The reason given was the human PBPK model was considered uncertain above inhalation concentrations of 500 ppm or 655 mg/m3. In Appendix B of the Methanol Toxicological Review (USEPA, 2013) on page B-34, Table B-6 provides the AUC values above background corresponding to a range of inhalation concentrations from 1 to 5000 ppm.

The human PBPK model can be summarized as the following equation presented in Appendix B:

The equation is not an exact match for the PBPK model but will be used here for convenience. In fact, we disagree with EPA’s claim that the model is too uncertain; at 500 ppm, there is a 0.7% difference between the model input and the value predicted by the equation; and, at 1000 ppm there is a 0.25% difference. These changes are negligible compared to the changes in the POD due to UF application. The table below shows the HEC predictions of the PBPK model compared to those developed with the above equation.

AUC (mg-hr/L)

HEC from full

model(ppm)

HEC Predicted with the

equation model(ppm)

Percent Difference

0.65 1 1.041 4.09%3.27 5 5.224 4.48%6.56 10 10.45 4.50%33.5 50 52.11 4.22%68.7 100 103.7 3.69%145 200 205.6 2.81%437 500 503.7 0.75%


11


1380 1000 997.5 -0.25%15400 2000 1974 -1.30%

115000 5000 4372 -12.56%

Hence, the equation model shown as Eq. 7 in the paper tends to be slightly underprotective at concentrations below 200 ppm and slightly overprotective at concentrations above 1000 ppm.

Methanol RfC: Approach 1—the IRIS DerivationThe composite UF was applied to the BMDL dose metric of 858 mg-hr/L. The result was 8.58 mg-hr/L as a human dose metric. Using the human PBPK model equation gave an HEC of 13.6 ppm or 18 mg/m3 rounded to 20 mg/m3.

6.1 Methanol RfC: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution

The composite UF was applied to the dose metric in rats and then expressed as an HEC with the model equation above.. The uncertainty in the dose metric was estimated as:

The overall uncertainty as the combination of the dose metric uncertainty and the composite UF applied to the POD yields:

The antilog of this result is 16.4 mg-hr/L. Application of the human PBPK model equation to obtain and HEC gives 25.9 ppm or 34 mg/m3 rounded to 30 mg/m3, 1.5 fold the IRIS result.

6.2 Methanol RfC: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

To the dose metric, a combination of the uncertainty in the dose metric and UFA was applied as follows:

The antilog of this value or 470 mg-hr/L is the human dose metric. The corresponding HEC is 531 ppm.

To this value are applied UFH and UFD as follows:


12


The antilog of this result is 41 ppm or 54 mg/m3. Rounding gives an RfD value of 50 mg/m3, 2.5-fold higher than the RfD from IRIS.


13


7 Reference Dose for 1,4-DioxaneLiver and kidney degeneration was chosen as the critical effect from Kociba et al. 1974). The NOAEL value of 9.6 mg/kg-d was chosen as the POD. The composite UF was 300, consisting of UFA =10, UFH = 10 and UFD = 3.

7.1 1,4-Dioxane RfD: Approach 1—the IRIS DerivationTo the POD of 9.6 mg/kg-d as a NOAEL was applied the composite UF to obtain an RfD value of 0.03 mg/kg-d.

7.2 1,4-Dioxane RfD: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

The composite UF was applied to the POD as follows:

The antilog of this value or 0.03 mg/kg-d becomes the RfD. This value is the same as that in the IRIS derivation.

7.3 1,4-Dioxane RfD: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

The application of the three UFs to the NOAEL in a staged fashion is:

The resulting RfD is the antilog of this result or 0.3 mg/kg-d, ten-fold higher than the IRIS value.


14


8 Reference Concentration for 1,4-DioxaneThe co-critical effects of atrophy and respiratory metaplasia of the olfactory epithelium were chosen. 1,4-dioxane acts as a Category 3 gas and produces extra-respiratory systemic effects. The ratio of the animal human blood:air partition coefficients was used as the dosimetric adjustment factor. The value was 1.12 rounded to 1, consistent with guidance in USEPA (2012). The duration-adjusted LOAEL with a value of 8.9 ppm or 32.2 mg/m3 was used as the POD. A composite UF of 1000, consisting of UFA = 3, UFH = 10, UFL = 10, and UFD = 3, was used.

8.1 1,4-Dioxane RfC: Approach 1—the IRIS DerivationTo the POD of 32.2 mg/m3 was applied the composite UF to obtain an RfC value of 0.03 mg/m3.

8.2 1,4-Dioxane RfC: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution

The composite UF was applied to the POD as follows:

The antilog of this value or 0.03 mg/m3 becomes the RfC. This value is the same as that in the IRIS derivation.

8.3 1,4-Dioxane RfC: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

The application of the four individual UFs to the LOAEL is:

The antilog of this result is 0.87 mg/m3 and would round to the RfC value of 0.9 mg/m3, and is thirty-fold higher than the IRIS value.


15


9 Reference Dose for BiphenylThe critical effect selected was papillary mineralization in the kidneys of male rats (Umeda et al., 2005). The BMD10 was 91.74 mg/kg/d and the BMDL10 was 58.44 mg/kg/d. Allometric scaling was used to estimate a dosimetric adjustment factor with a value of 0.24. A composite UF of 30 was applied, consisting of UFA = 3 and UFH = 10.

9.1 Biphenyl RfD: Approach 1—the IRIS DerivationThe BMDL10 value of 58.44 mg/kg/d was multiplied by the DAF of 0.24r and the result divided by the composite UF of 30 to obtain the RfD of 0.5 mg/kg/d.

9.2 Biphenyl RfD: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

The uncertainty in the DAF-adjusted BMD is

Applying this uncertainty and the composite UF to the BMD gives

The antilog of this value is 0.72 rounded to 0.7mg/kg-d, slightly higher than the IRIS value.

9.3 Biphenyl RfD: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

As noted the DAF is applied first, so the RfD is calculated as:

The antilog of this result is 1.7 mg/kg-d, rounded to 2 mg/kg-d, which is four times higher than the IRIS value.


16


10 Reference Dose for TCDDThe critical effects were decreased sperm counts in men exposed to TCDD as boys and increased TSH in neonates. Both human studies were conducted on the Seveso cohort. PBPK modeling was used to estimate external doses from lipid-normalized serum concentrations. The LOAEL used was 2E-08 mg/kg-d. The composite UF was 30, consisting of UFL = 10 and UFH = 3.

10.1 TCDD Approach 1—the IRIS DerivationThe composite UF was applied to the LOAEL to obtain the RfD of 7E-10 mg/kg-d.

10.2 TCDD Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

The LOAEL was expressed as a natural logarithm and the composite UF applied as a standard deviation in log space as follows:

The antilog of the result is 7E-10 mg/kg-d, the same as the IRIS derivation.

10.3 TCDD RfD: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

UFH and UFL were applied to the POD as follows:

The antilog of this result is 1.6E-09 mg/kg-d, rounding to 2E-09 mg/kg-d, about three-fold higher than the IRIS result.


17


11 Reference Concentration for Tetrachloroethylene (PCE) hereThe critical effect chosen was the occurrence of neurological effects in humans observed in Echeverria et al. (1995) and Cavalleri et al. (1994). LOAELs were identified in both studies. The LOAEL from Echeverria et al. (1995) was 56 mg/m3 and that from Cavalleri et al. (1994) was 15 mg/m3. The composite UF was 1000, consisting of UFL = 10, UFH = 10, and UFD = 10. The final RfC equal to 0.04 mg/m3 was chosen as the midpoint between the two RfCs derived from the two studies.

11.1 Tetrachloroethylene RfC: Approach 1—the IRIS DerivationTo each of the candidate LOAELs was applied the composite UF of 1000. The resulting values were 0.015 and 0.056 mg/m3. The midpoint of the range is 0.0355, rounded to 0.04 mg/m3.

11.2 Tetrachloroethylene RfC: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution

Here the variance-weighted POD of exp(3.379) or 29 mg/m3 with a standard deviation of 0.1987 will be used. The derivation of this POD from two studies is shown in the paper.

This value is below the IRIS value. The reason is that combining the natural logs of the PODs by variance-weighting, yields a lower result than averaging the two candidate RfD values, likely due to the compression of higher values in log space.

11.3 Tetrachloroethylene RfC—Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

This evaluation will be a variant of Approach 2 that combined two studies in a Bayesian framework. The individual uncertainty factors are applied singly rather than as a composite.

The antilog of this result would be 0.53, rounded to 0.5 mg/m3, twelve-fold higher than the IRIS value.


18


12 Reference Dose for PhenolThe critical effect was decreased maternal weight gain in rats with a BMD1SD of 157 mg/kg-d and a BMDL1SD of 93 mg/kg-d. A composite UF of 300 was used. The individual UFs were: UFA = 10, UFH = 10, and UFD = 3.

12.1 Phenol RfD: Approach 1—the IRIS DerivationThe composite UF was applied to the BMDL to obtain the RfD of 0.3 mg/kg-d.

12.2 Phenol RfD: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

This calculation is shown on page 121 of NRC (2014). The resulting RfD is 0.51 mg/kg-d, rounded to 0.5 mg/kg-d, about 40% higher than the IRIS RfD.

12.3 Phenol RfD: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

This calculation is shown as Eq. 4 in the report. The resulting RfD is 5 mg/kg-d, over ten-fold higher than the IRIS value.


19


13 Reference Dose for DIchloromethaneThe critical effect was liver toxicity (vacuolation and development of foci) in rats. The POD was the 1st percentile of the HED. A PBPK model was used to obtain rat internal doses. The internal dose metric was adjusted with a DAF based on allometric scaling to obtain a human-equivalent internal BMDL10. Human external doses were estimated with a probabilistic PBPK model developed using Bayesian Markov Chain Monte Carlo. The composite UF was 30, consisting of UFA = 3, UFH = 3, and UFD = 3.

13.1 Dichloromethane RfD: Approach 1—the IRIS DerivationBMD modeling was conducted on internal doses in rats representing the amount of DCM metabolized. The internal BMD10 is 70.69 mg DCM metabolized / L liver / day and the BMDL10 is 51.42. Although the DCM Toxicological Review (USEPA, 2011b) indicated the value of the DAF was 4.09, the value of 3.863 appears to have been used to obtain the human BMDL10 of 13.31 (Table 5-3 on p. 180 of USEPA, 2011b). The first percentile of the distribution of the HED was 0.189 mg/kg-d. To this value was applied the composite UF of 30 to give the RfD of 6E-03 mg/kg-d

13.2 Dichloromethane RfD: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

The MCMC human PBPK model provides the distribution for the HED corresponding to the internal BMDL10. Using the DAF, the internal BMD10 in humans can be calculated as:

To obtain the HED distribution corresponding to this value, the human data were graphically extracted from Figure 5-3 in the DCM Toxicological Review. Polynomials passing through the origin were fit to the human mean, the human 5th and the human 95th percentiles. These fitted polynomials are not a preferred option. Ideally, EPA would have provided response surface data in a table. The fits of the polynomials are shown in the plot below.


20


The polynomials corresponding to the three plots are:

Human mean (green symbols): y = -0.0329 x2 + 14.291 x Human 95th percentile (red symbols): y = -0.0269 x2 + 9.9117 x Human 5th percentile (purple symbols): y = -0.0484 x2 + 20.913 x

The mean, 5th percentile and 95th percentile of the HED corresponding to the internal BMD of 18.29 are 1.286, 0.8756 and 1.857 mg/kg-d respectively. The distribution of the HED at the internal BMD can be approximated by a lognormal distribution with = 0.2515 and = 0.3759. The first percentile of this distribution is 0.5364 mg/kg-d. The choice of the first percentile is needed to account for GST polymorphisms in the population (Chapter 3 in USEPA, 2011b).

Thus, the 1st percentile HED from the BMDL10 is 0.189 mg/kg-d and the 1st percentile HED from the BMD10 is 0.5364 mg/kg-d

The standard deviation in the POD as the 1st percentile HED is thus

The uncertainty in the POD and the composite UF are combined and applied as follows:

The antilog of this result or 0.015, rounded to 0.02 mg/kg-d becomes the RfD. The value is three-fold higher than that in IRIS.


21


13.3 Dichloromethane RfD: Approach 3—Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

Application of the DAF to the internal BMD10 and BMDL10 resulted in 18.29 and 13.31 mg metabolized as the respective values. The standard deviation in the POD is thus:

The uncertainty in the BMD and UFA were applied as follows:

The antilog of this value is 5.827 and represents the human internal dose metric to be converted into an HED distribution. Using the polynomials shown in Approach 2, the mean HED is 0.407 mg/kg/d and the 5th percentile HED is 0.281 mg/kg/d. Assuming these values are lognormally distributed allows one to estimate the first percentile would be 0.241 mg/kg/d.


The antilog of this result is 0.051 mg/kg-d, rounded to 0.05 mg/kg-d would be the RfD, almost an order of magnitude greater than the IRIS value.


22


14 Reference Concentration for DichloromethaneThe critical effect was hepatotoxicity in rats observed in a two-year inhalation study. Animals were exposed for 6 hours/day and 5 days/week. A PBPK model was used to convert external doses into the same dose metric used for RfD development, mg DCM metabolized per L liver per day. BMD modeling was used to obtain a BMD10 and BMDL10 in terms of the dose metric. The BMDL10 was converted to a human equivalent using an allometric DAF. Human external doses were estimated with a probabilistic PBPK model developed using Bayesian Markov Chain Monte Carlo. The composite UF was 30, consisting of UFA = 3, UFH = 3, and UFD = 3.

14.1 Dichloromethane RfC: Approach 1—the IRIS DerivationBMD modeling was conducted on internal doses in rats representing the amount of DCM metabolized. The internal BMD10 is 737.93 mg DCM metabolized / L liver / day and the BMDL10 is 531.82. A DAF of 4.09 was determined by allometric scaling to obtain a human-equivalent BMDL10 of 130.03 mg metabolized. The first percentile of the distribution of the HEC was 17.2 mg/m3. To this value was applied the composite UF of 30 to give the RfC of 0.6 mg/m3.

14.2 Dichloromethane RfC: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution

The MCMC human PBPK model provides the distribution for the HEC corresponding to the internal BMD10 and BMDL10. The human internal BMDL10 is 130.03 mg metabolized. Using the DAF, the internal BMD10 in humans can be calculated as 737.93/4.09 = 180.42 and, as noted above, the BMDL10 was 531.82/4.09 = 130.03

To obtain the HEC distribution corresponding to this value, the human data were graphically extracted from Figure 5-7 in the DCM Toxicological Review. Polynomials passing through the origin were fit to the human mean, the human 5th and the human 95th percentiles. A response surface would have been preferred. These are shown in the plot below.


23


The polynomials corresponding to the three plots are: Human mean (blue symbols): y = 7.0E-06 x3 – 0.0163 x2 + 12.192 x Human 95th percentile (red symbols): y = 1.0E-05 x3 – 0.009 x2 + 5.4405 x Human 5th percentile (purple symbols): y = 5.0E-06 x3 – 0.0251 x2 + 21.993 x

The mean and 5th percentile HEC corresponding to the internal BMD of 180.42 are 15.1 and 8.28 ppm respectively. These values correspond to 52.3 and 28.7 mg/m3. The mean and 5th percentile HEC corresponding to the internal BMDL of 130.03 are 10.8 and 5.95 ppm respectively, corresponding to 37.5 and 20.6 mg/m3 based on the polynomials above. USEPA (2011b) provides these values for the BMDL as 48.5 and 21.3 mg/m3, indicating a difference between the polynomials used here and the actual PBPK model. The acslXtreme model code is provided in Appendix J of USEPA (2011b). However, getting the model up and running was beyond the scope of this exercise and unnecessary for its purpose—to demonstrate the application of UFs with Bayesian methods for a variety of chemical assessments.

The distribution of the HEC in mg/m3 at the internal BMD can be reasonably approximated by a lognormal distribution with = 3.957 and = 0.3664. Using these values, the first percentile of this distribution is 22.3 mg/m3. The choice of the first percentile is needed to account for GST polymorphisms in the population (Chapter 3 in USEPA, 2011b).

Thus, the 1st percentile HED from the BMDL10 is 17.2 mg/m3 from Table 5-7 in the Toxicological Review and the 1st percentile HED from the BMD10 is 22.3 mg/m3 from the calculation above.

The standard deviation in the POD is thus


24


The uncertainty in the POD and the composite UF are combined and applied as follows:

The antilog of this result or 0.73 mg/m3, rounded to 0.7 mg/m3, becomes the RfD. The value is essentially the same as the RfD in IRIS.

14.3 Dichloromethane RfC: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

Application of the DAF to the internal BMD10 and BMDL10 resulted in 180.42 and 130.03 mg metabolized as the respective values. The standard deviation in the POD is thus:

The uncertainty in the BMD and UFA were applied as follows:

The antilog of this value is 57.3 and represents the human internal dose metric to be converted into an HEC distribution. Using the polynomials shown in Approach 2, the mean HED is 16.4 mg/m3 and the 5th percentile HED is 9.06 mg/m3. From these, the first percentile would be 7.08 mg/m3, assuming the HEC distribution is lognormal.


The antilog of this result is 1.51 mg/m3, rounded to 1.5 mg/m3 would be the RfC, over two-fold higher than the IRIS value.


25


15 Reference Dose for Trichloroacetic AcidThe critical effect was hepatocellular necrosis observed in mice in a chronic study. The BMDL10 was chosen as the POD and the composite UF was 1000, consisting of UFA = 10, UFH = 10 and UFD = 10.

15.1 TCA RfD: Approach 1—the IRIS DerivationThe BMDL10 of 18 mg/kg-d was selected as the POD. To this value was applied the composite RfD of 1000 to obtain the RfD of 0.02 mg/kg-d.

15.2 TCA RfD: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

The BMD10 for the critical effect was 40.7 mg/kg-d and the BMDL10 was 17.9 mg/kg-d. Hence, the standard deviation of the POD is

The uncertainty in the POD and the composite UF were applied as follows:

The rounded antilog of this result is 0.04 mg/kg-d and would be the RfD, twice the IRIS value.

15.3 TCA RfD: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

The uncertainty in the POD was combined with individual UFs as follows:

The rounded antilog of this result is 0.7 mg/kg-d and becomes the RfD. This value is 35 times greater than the IRIS value.


26


16 Reference Dose for HexachloroethaneThe critical effect was atrophy and degeneration of renal tubules in male rats observed in a subchronic study (Gorzinski et al., 1985). The POD was obtained by BMD modeling. The composite UF was 1000, consisting of UFA = 10, UFH = 10, UFS = 3, and UFD = 3.

16.1 Hexachloroethane RfD: Approach 1—the IRIS DerivationThe BMD10 was 1.34 mg/kg-d and the BMDL10 was 0.728 mg/kg-d. To this value was applied the composite UF of 1000 to obtain the RfD of 7E-04 mg/kg-d.

16.2 Hexachloroethane RfD: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

The standard deviation of the uncertainty in the BMD was calculated as

This value was combined with the composite UF to calculate the RfD as follows:

The antilog of this result is 0.0013 rounded to 0.001 mg/kg-d is the RfD value and is about 40% higher than the IRIS result.

16.3 Hexachloroethane RfD: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

In this Approach, the UFs were applied to the BMD along with the uncertainty in the POD as follows:

The antilog of this result is 0.032 rounded to the RfD of 0.03 mg/kg-d, 43 times higher than the IRIS value.


27


17 Reference Concentration for HexachloroethaneThe critical effect was neurological effects in rats. The NOAEL was 465 mg/m3. This value was adjusted for continuous exposure to obtain the POD of 83 mg/m3. Hexachloroethane was considered a Category 3 gas and a regional gas dose ratio of 1 was used as a DAF. The composite UF was 3000, consisting of UFA = 3, UFH = 10, UFS = 10, and UFD = 10.

17.1 Hexachloroethane RfC: Approach 1—the IRIS DerivationThe composite UF was applied to the DAF-adjusted POD to obtain the RfD of 0.03 mg/m3.

17.2 Hexachloroethane RfC: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

The composite UF was applied to the duration- and DAF-adjusted POD as follows:

The antilog of this result rounds to 0.03 mg/m3, the same as the IRIS value.

17.3 Hexachloroethane RfC: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

Following duration-adjustment, UFS was applied to the POD as follows:

Application of the DAF=1 would not change this value and the other three UFs were applied:

The antilog of this result is 0.27, which would round to 0.3 mg/m3, an order of magnitude higher than the IRIS value.


28


18 Reference Dose for AcrylamideThe critical effect was degenerative nerve changes observed in a chronic study of rats. BMD modeling was used to obtain a BMDL5 of 0.053 mg/kd-d. An AUC value for acrylamide and its metabolite glycidamide based on the relationship between hemoglobin (Hb) adducts and administered dose in both rats and humans. This relationship was used to estimate an AUC in humans and to estimate a human-equivalent dose corresponding to the BMDL. The use of Hb adducts for species extrapolation is considered equivalent to the use of a PBPK model or DAF. The composite UF was then applied to the HED. The composite UF consisted of UFA-TD = 3 and UFH = 10.

18.1 Acrylamide RfD: Approach 1—the IRIS DerivationThe BMD5 for male rats was 0.58 mg/kg-d and the BMDL5 was 0.27 mg/kg-d. The BMDL5 value was converted to an AUC for acrylamide in blood with the conversion factor of 27.4 as follows:

Details of the derivation of the conversion factor can be found on pp. 205-214 of the Toxicological Review (USEPA, 2010). The HED was calculated with a similar conversion in humans.

The composite UF of 30 was applied to this result to obtain the RfD of 0.002 mg/kg-d.

18.2 Acrylamide RfD: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

The HED BMD was estimated as 0.113 mg/kg-d from the rat BMD, using the two conversions shown above. The uncertainty in the HED BMD is given by

The entire uncertainty was applied to the HED BMD as


29


The antilog of this result is 0.0035 mg/kg-d, which would round up to 0.004 mg/kg-d, two fold higher than the value in IRIS.

18.3 Acrylamide RfD: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

The BMD and BMDL expressed as an AUC in rats are 15.9 and 7.4 M-hr respectively (page 214 in USEPA, 2010). The SD of the BMD distribution in log space is 0.4649.

The uncertainty in the BMD as an AUC and remaining animal-to-human extrapolation would be calculated as

The antilog of this value or 4.17 M-hr represents the human BMD as an AUC. The human conversion factor is used to obtain an HED.

UFH is applied as follows:

The antilog of this result is 0.003 mg/kg-d, about thirty percent higher than the value in IRIS.


30


19 Reference Concentration for ChloropreneThe co-critical effects were an increase in the incidence of olfactory atrophy in male rats, alveolar hyperplasia in female rats and splenic hemapoetic proliferation in female mice observed in a chronic study. The POD used was a BMDL-HEC.

The BMD10 and BMDL10 for olfactory atrophy in male rats were 4.9 and 3.5 ppm. The BMD10 and BMDL10 for alveolar hyperplasia in female rats were 4.9 and 3.3 ppm. The BMD10 and BMDL10 for splenic hematopoetic proliferation in female mice were 4.0 and 3.3 ppm. The mice were exposed for 6 hr per day and five days a week for two years. The three duration-adjusted PODs were 2.3, 2.1 and 2.1 mg/m3. Chloroprene is considered a Category 3 gas. The calculated DAF is 1.7 and the default value of 1 was substituted. The composite UF was 100, consisting of UFA = 3, UFH = 10 and UFD = 3.

19.1 Chloroprene RfC: Approach 1—the IRIS DerivationTo the estimate of the three duration-adjusted PODs = 2 mg/m3 was applied the composite UF of 100 to obtain the RfD of 0.02 mg/m3.

19.2 Chloroprene RfD: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution

The standard deviations of the three PODs were calculated as the difference in the BMD and BMDL values divided by 1.645. The lowest duration-adjusted BMD was based on splenic hematopoetic proliferation in female mice with a value of 2.59 mg/m3 with the VMDL 0f 2.13 mg/m3. The standard deviation on a natural log scale would be 0.1169.

This POD was combined with the other two identical duration-adjusted PODs of 3.17 mg/m3 for nasal atrophy in male rats and alveolar hyperplasia in female rats. The BMDLs were 2.26 and 2.13 mg/mg3 respectively. From Eq. 9b in the paper, the combined standard deviation would of these two rat PODs would be 0.1558 on a natural log scale. Using the mouse data as a prior and combining with the rat data using Eq. 9a, one obtains

The combined variance in the POD is


31


The uncertainty in the POD can be combined with the composite UF and applied to the POD.

The antilog of this result is 0.03 mg/m3, slightly higher than the IRIS value.

19.3 Chloroprene RfC: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

Because the DAF was 1, the POD was adjusted with all sources of uncertainty combined.

The antilog of this result was adjusted with the DAF=1 resulting in no change.

UFH and UFD were then applied to this result.

The antilog of this result is 0.08 mg/m3. This value is four-fold higher than the IRIS value.


32


20 Reference Dose for cis-1,2-DichloroethyleneThe critical effect was increased kidney weights in male rats observed in a subchronic oral study. BMD modeling was used to obtain the POD. The composite UF was 3000 and consisted of UFH = 10, UFA = 10, UFS = 10 and UFD = 3.

20.1 cis-1,2-DCE RfD: Approach 1—the IRIS DerivationThe BMD10 and BMDL10 values were 19.8 and 5.1 mg/kg-d respectively. The composite UF was applied to the BMDL10 to obtain the RfD of 0.002 mg/kg-d.

20.2 cis-1,2-DCE RfD: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

The uncertainty in the POD was

This SD and the SD of the composite UF were applied to the POD as follows:

The rounded antilog of this result is 0.006 mg/kg-d, the RfD value by this approach, three-fold higher than the IRIS value.

20.3 cis-1,2-DCE RfD: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

The uncertainty in the POD and the individual UFs were applied as follows:

The antilog of this result is 0.255, which would round to 0.3 mg/kg-d, which is 150-fold higher than the IRIS result.


33


21 Reference Dose for trans-1,2-DichloroethyleneThe critical effect is a decrease in antibody-forming cells in male mice observed in a subchronic oral study. The BMDL1SD was used as the POD. The composite UF of 3000 was applied to the POD and consisted of UFH = 10, UFA = 10, UFS = 10, and UFD = 3.

21.1 trans-1,2-DCE RfD: Approach 1—the IRIS DerivationThe BMDL1SD was 65 mg/kg-d was used as the POD. The composite UF was applied directly to the POD to obtain the RfD of 0.02 mg/kd-d.

21.2 trans-1,2-DCE RfD: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

The BMD1SD was 125.6 mg/kg-d and the BMDL1SD was 65.0 mg/kg-d. The uncertainty in the POD is


The antilog of this result is 0.041 mg/kg-d. The resulting RfC would be 0.04 mg/kg-d, twice that of the IRIS value.

21.3 trans-1,2-DCE RfD: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

The uncertainty in the POD and the individual UFs were applied as follows:

The antilog of this result is 1.9, which would round to 2 mg/kg-d, two orders of magnitude higher than the IRIS result.


34


22 Reference Dose for Pentachlorophenol (PCP)The critical effect was hepatotoxicity observed in beagle dogs in a one-year chronic study. A LOAEL of 1.5 mg/kg/d was identified as the POD. A composite UF of 300, consisting of UFH = 10, UFA = 10, and UFL = 3.

22.1 PCP RfD: Approach 1—the IRIS DerivationThe composite UF was applied to the LOAEL POD to obtain the RfD of 0.005 mg/kg-d.

22.2 PCP RfD: Approach 2— Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

The composite UF was applied to the LOAEL as

The antilog of this result is 0.005 mg/kg-d, the same as the IRIS value.

22.3 PCP RfD: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

The UFs were applied as follows:

The antilog of this value is 0.048 rounded to 0.05 mg/kg-d, an order of magnitude higher than the IRIS value.


35


23 Reference Dose for 1,1,2,2-TetrachloroethaneThe critical effect was increased relative liver weight in female rats in a subchronic study. The POD was the BMDL1SD. A composite UF of 1000 was used, consisting of UFA = 10, UFH = 10, UFS = 3 and UFD = 3.

23.1 1,1,2,2-Tetrachloroethane RfD: Approach 1—the IRIS DerivationThe composite UF was applied directed to the BMDL1SD of 15 mg/kg-d to obtain the RfD of 0.02 mg/kg-d.

23.2 1,1,2,2-Tetrachloroethane RfD: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

The BMD1SD was 22 mg/kg-d and the BMDL1SD was 15 mg/kg-d. The standard deviation in log space from these values is


The antilog of this result is 0.022 mg/kg-d. The resulting RfC would be 0.02 mg/kg-d, the same as the IRIS value.

23.3 1,1,2,2-Tetrachloroethane RfD: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

The uncertainty in the POD and that in the individual UFs were applied as:

The antilog of this result is 0.58 mg/kg-d, rounded to 0.6 mg/kg-d becomes the RfD, thirty-fold higher than the IRIS value.


36


24 Reference Concentration for Carbon TetrachlorideThe critical effect was fatty changes in the liver observed in a chronic inhalation study of rats. Internal doses were estimated with a PBPK model. The dose metric was time-averaged rate of metabolism of CCl4 in the liver. A human PBPK model was used to estimate HECs from the internal dose metric. The BMCL10-HEC of 14.3 mg/m3 was used as the POD. The composite UF was 100, consisting of UFA = 3, UFH = 10, and UFD = 3.

24.1 Carbon Tetrachloride RfC: Approach 1—the IRIS DerivationA PBPK model was used to convert the air concentrations in the animal study to the dose metric. BMD modeling was performed on the dose metric values. In the PBPK model, the dose metric is termed MRANKL, the time-averaged rate of metabolism in units of mol/hr-kg.

The BMD10 and BMDL10 were 3.257 and 2.586 mol/hr-kg for rat Vmax = 0.4 and 4.600 and 3.653 mol/hr-kg for a rat Vmax = 0.65. For the human PBPK model, the value for Vmax was 1.49 derived from human in vitro data. The HECs corresponding to the two rat BMCLs were 11.826 and 16.794 respectively. These were averaged to obtain the HEC of 14.3 mg/m3. Applying the composite UF of 100 gave 0.143 mg/m3, rounded to 0.1 mg/m3.

24.2 Carbon Tetrachloride RfC: Approach 2—Application of the Composite UF as the Standard Deviation of a Bayesian Prior Distribution per NRC (2014)

In order to estimate the HEC corresponding to the BMC, a model was developed from the information in Appendix C of the Toxicological Review. The model predicts the HEC in mg/m3 from MRANKL, the time-averaged rate of metabolism. The model is a single equation as follows:

The HEC-BMC and HEC-BMCL are 18.1 and 14.3 mg/m3 respectively. Hence, the uncertainty in the POD is

This value was combined with the composite UF and applied to the POD.


37


The antilog of this result is 0.18 mg/m3 rounded to 0.2 mg/m3 becomes the RfC, twice that in IRIS.

24.3 Carbon Tetrachloride RfC: Approach 3— Application of Individual UFs as the Standard Deviations of Bayesian Prior Distributions

The uncertainty in the two PODs expressed as MRANKL are

The uncertainty in the dose metrics shown above was applied with UFA.

The antilogs of these two results are 1.060 and 1.497 mol/hr-kg. The corresponding HECs were calculated with the single equation model are 4.812 and 6.812 mg/m3. The average of these two values is 5.831 mg/m3. To this value was applied UFH and UFD as follows:

The antilog of this result is 0.453 mg/m3 rounded to 0.5 mg/m3 is the RfD by this approach, five-fold higher than the IRIS value.

25 Data-Derived Distributions for Lognormal Standard Deviations for UFs

Supplementary Table 1 provides estimates of prior standard deviations for the various UFs based on information from the scientific literature. An effort was made to provide starting values and notes about the calculation method so that readers could recreate these calculations. The values of these data-derived UFs are discussed further in the sections below and compared to the long abused default values. A summary of the comparisons between data-derived and default UFs are summarized in Supplementary Table 2.


38


26 References for Supplementary ContentKorsak, Z., Wiśniewska-Knypl, J., Swiercz, R., 1994. Toxic effects of subchronic

combined exposure to n-butyl alcohol and m-xylene in rats. Int J Occup Med Environ Health. 7, 155-66

National Toxicology Program, N. T. P., 2002. NTP toxicology and carcinogensis studies of vanadium pentoxide (CAS No. 1314-62-1) in F344/N rats and B6C3F1 mice (inhalation). Natl Toxicol Program Tech Rep Ser. 1-343

Sitarek, K., Berlińska, B., Barański, B., 1994. Assessment of the effect of n-butanol given to female rats in drinking water on fertility and prenatal development of their offspring. Int J Occup Med Environ Health. 7, 365-70

Teeguarden, J. G., Deisinger, P. J., Poet, T. S., English, J. C., Faber, W. D., Barton, H. A., Corley, R. A., Clewell, H. J., 2005. Derivation of a human equivalent concentration for n-butanol using a physiologically based pharmacokinetic model for n-butyl acetate and metabolites n-butanol and n-butyric acid. Toxicol Sci. 85, 429-46.10.1093/toxsci/kfi103

Umeda, Y., Aiso, S., Yamazaki, K., Ohnishi, M., Arito, H., Nagano, K., Yamamoto, S., Matsushima, T., 2005. Carcinogenicity of biphenyl in mice by two years feeding. J Vet Med Sci. 67, 417-24

USEPA, Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry. Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry, 1994.

USEPA, Toxicological Review of Acrylamide. USEPA, Washington, DC, 2010.USEPA, IRIS Toxicological Review of n-Butanol (External Review Draft, 2011).

USEPA, 2011a.USEPA, Toxicological Review of Dichloromethane (Methylene Chloride). USEPA,

Washington, DC, 2011b.USEPA, Benchmark Dose Technical Guidance. Benchmark Dose Technical Guidance.

USEPA, 2012.USEPA, IRIS Toxicological Review of Methanol (noncancer). IRIS Toxicological

Review of Methanol (noncancer). USEPA, 2013.


39


Supplementary Table 1. Standard deviations of lognormal distributions representing each of the five UFs. WHO-IPCS (2014) provides data-derived values for all UFs except for LOAEL-to-NOAEL extrapolation. Values are developed from up to three data sources.UF / EF Source #1 Source #2 Source #3 WHO Guidance recommendationUncertainty in the NOAEL when used as the POD

Continuous Chronic or subchronic oral: = -1.1, = 0.9511 (P05=0.07 and P95 = 1.6)Continuous Developmental oral: = -1.1, = 1.164 (P05=0.05 and P95=2.3)Quantal Developmental Oral (deterministic): = -1.5, = 1.007 based on P05=0.04 and P95=1.1Quantal Developmental Oral (stochastic): = -1.1, = 0.2513 based on P05=0.14 and P95=0.32Table 4.1, p. 41, WHO-IPCS (2014)

LOAEL-to-NOAEL

GM = 4.5, GSD = 5.6 = 1.5, = 0.5306 (n=175)Table 3 in Pieters et al. (1998)GM = 3.5, GSD = 1.38 = 1.25, = 0.599Table 1 in Hasegawa et al. (2010)

The value of the LOAEL/NOAEL ratio reflects study design and the LOAEL should not be used as a POD (e.g.

Subchronic-to-chronic

GM = 1.7, GSD = 5.6 = 0.53, = 1.723 (n = 149) Table 1 in Pieters et al. (1998)GM = 1.7, GSD = 3.3 = 0.53, = 1.193Hasegawa et al. (2010)

GM = 1.2, GSD = 3.3 = 0.18, =1.2 (n = 68) NOAELs in Table 4 of Bokkers and Slob (2005)

GM = 1.7, GSD = 2.9 = 0.53, = 1.1CEDs in Table 4 ofBokkers and Slob (2005)

Subchronic-> chronic: = 0.693, = 0.8427(P05=0.5 and p95=8) (Table 4.2, p. 43)subacute -> chronic: = 1.61, = 1.264(P05=5/8 and p95=40) (Table 4.2, p. 43)WHO-IPCS (2014)

Interspecies, TD and TK combined

= 0.98, = 1.329 (n = 161)mouse: =2.041, =0.9189 (n=54)rat: =1.099, =1.306 (17)monkey: =0.9163, =0.7692 (n=34)dog: =0.0, =1.156 (n=46)bootstrapped from median and P90 data in Table 2 of Price et al. (2008)

GM = 2.01, GSD = 3.44 = 0.7, = 1.235 (n = 228)NOAELS from Table 2, first column in Bokkers and Slob (2007)

GM = 1.8 GSDcorrected = 2 = 0.7, = 0.693 (n=368)CEDs from first column of Table 2, first column in Bokkers and Slob (2007)

Both TK and TD after adjustment for body size = 0, = 0.6682 (P05=1/3 and P95=3) (Table 4.5, p. 45)WHO-IPCS (2014)

Intraspecies GM = 3.0, GSD = 1.38 = 1.1, = 0.322Table 1 in Hasegawa et al. (2010)

Combined: dependent on degree of population coverage;90% coverage, = 0.96, = 0.49095% coverage, = 1.23, = 0.62999% coverage, = 1.74, = 0.89099.9% coverage, = 2.31, = 1.1899.99% coverage, = 2.77, = 1.42Table 4.5 p. 49 WHO-IPCS (2014)

Database Deficiencies

Chronic/reproductive = -0.93, = 1.63 (n = 146)Table 1 in Blackburn et al. (2015)

Chronic/developmental = -1.96, = 2.19 (n = 142)Table 1 in Blackburn et al. (2015)

Not considered


1

Documents

FOR Simon ET AL - ars.els-cdn.com€¦ · Web viewThe relationship between exposure concentration and steady state blood concentration in humans is linear as shown in Figure S1