Final Draft
Drinking Water Contaminants of Emerging Concern Program
Special Project: Evaluating, Testing, and Reporting of Alternative Risk Assessment Methods
Selection, Evaluation and Recommendations of Viable Alternative Risk Assessment Methods for the Development of
Drinking Water Guidance Values
Prepared for: Minnesota Department of Health Contaminants of Emerging Concern (CEC) Program Environmental Health Division 625 N. Robert Street St. Paul, MN 55164
Prepared by: Jeff Stevens, PhD J.B. Stevens & Associates 8477 Rice Lake Road Maple Grove, MN 55369
Submitted: July 25, 2012
[Note: MDH staff have made limited revisions to this report for the sake of clarity, correction, or formatting. This report does not represent official agency policy but may be used to inform future work.] ABBREVIATIONS AND ACRONYMS
ALAP As Low As Practical
ALARA As Low As Reasonably Achievable
B(a)P Benzo(a)pyrene
CalEPA California Environmental Protection Agency
CEC Contaminants of Emerging Concern
CPSC Consumer Product Safety Commission
DNA Deoxyribonucleic acid
DOE US Department of Energy
EF Extrapolation Factor
EU European Union
FAO Food and Agriculture Organization of the United Nations
FDA US Food and Drug Administration
HBV Health Based Value
HGPRT Hypoxanthine-guanine phosphoribosyl transferase
HPV High Production Volume
HRL Health Risk Limit
HSDB Hazardous Substance Data Bank
ICRP International Commission on Radiological Protection
LD50 Lethal Dose for 50% of the Test Animals
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LOAEL Lowest Observed Adverse Effect Level
LTD Lowest Therapeutic Dose
OPI Organophosphate Insecticide
OSHA Occupational Safety and Health Administration
OTC Over-the-counter
MA Massachusetts
MCL Maximum Contaminant Level
MDH Minnesota Department of Health
MI DEQ Michigan Department of Environmental Quality
MOE Margin of Exposure
MSDS Material Safety Data Sheet
MTD Maximum Tolerated Dose
NCI National Cancer Institute
NIEHS National Institute of Environmental Health Sciences
NOAEL No Observable Adverse Effect Level
NTP National Toxicology Program
NRC National Research Council
NSRL No Significant Risk Level
NY New York
OECD Organization for Economic Co-operation and Development
OSHA Occupational Safety and Health Administration
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PAH Polycyclic Aromatic Hydrocarbons
PCBs Polychlorinated Biphenyls
PCDD/F Polychlorinated dibenzo-p-dioxin/ Polychlorinated dibenzofuran
PFOA Perfluorooctanoic acid
PFOS Perfluorooctane sulfonate
POC Principal Organic Contaminants
QA/QC Quality Assurance/Quality Control
QSAR Qualitative/Quantitative Structure Activity Relationships
RAA Risk Assessment Advice
REACH Registration, Evaluation, Authorization and Restriction of Chemical Substances
RfD Reference Dose
RSC Relative Source Contribution Factor
SF Slope Factor
TCDD 2,3,7,8-Tetrachlorodibenzo-p-dioxin
TD10 Toxic Dose for 10% of the Test Animals
TD50 Toxic Dose for 50% of the Test Animals
TK Thymidine Kinase
TOC Total Organic Carbon
TTC Threshold of Toxicological Concern
UCL Upper Confidence Limit
UDS Unscheduled DNA Synthesis
UF Uncertainty Factor
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US EPA US Environmental Protection Agency
WHO World Health Organization
WRF WateReuse Research Foundation
VSD Virtual Safe Dose
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EXECUTIVE SUMMARY
Over the past several years a variety of non-environmentally regulated chemicals have started to be detected in both groundwater and surface water throughout the US, including Minnesota. As a group, these chemicals have been termed “Contaminants of Emerging Concern” (CEC). The majority of these CECs have been shown to be pharmaceuticals, personal and household care product ingredients and endocrine disrupting compounds such as birth control product chemicals. The Minnesota Department of Health (MDH) has formed a program within the Division of Environmental Health to specifically address these water contaminants (CEC Program).
One effort by this Program is a Clean Water, Land and Legacy Amendment-funded special project entitled “Evaluating, Testing, and Reporting of Alternative Risk Assessment Methods.” The goal of this project is to present defensible alternative risk assessment methodologies for deriving water quality advisory criteria for CECs. Alternative risk assessment methodologies were sought for the CEC Program because of:
• the large number of CECs being detected each year (due to both increased analytical sensitivity and a current focus on these chemical classes), • a paucity of requisite toxicological information on CECs that is necessary to develop drinking water guidance (HRL/HBV/RAA) by the traditional risk assessment approach, and • the amount of time and effort required to perform a traditional toxicity assessment on each chemical.
The initial phase of this special project focused on identifying candidate alternative risk assessment methods. The criteria used for selecting these alternative methods was that they be capable of deriving ‘safe harbor’ criteria and as a group be able to address the majority of CECs that have been reported in drinking water, regardless of the composition of their existing toxicity databases.
A total of ten candidate alternative risk assessment methods were identified in this initial project phase (see Chapter 2). These methods are:
• As Low As Reasonably Achievable Approach • LD50 Extrapolation Approach • Margin of Exposure Approach • Lowest Therapeutic Dose Approach • Percent Sample Mass Approach • Percentile Approach • Quantitative/Qualitative Structure-Activity Relationship Approach • Surrogate Compound Approach • Threshold of Toxicological Concern Approach • Virtual Safe Dose Approach
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The second phase of this project involved a technical evaluation of each of these candidate methods (see Chapter 3). Each evaluation began with a brief description of the method, followed by a summary of any background information on the procedure (e.g., how and where it had been used previously). This introductory information was then followed by a quantitative method analysis, when possible, and finally a strengths and limitations analysis with respect to its usefulness to the CEC Program. Each evaluation concluded with a recommendation regarding whether or not the method should be retained for further evaluation by the CEC Program.
Out of the original 10 candidate alternative risk assessment methods, six have been recommended for further evaluation in the CEC Program. The six potential CEC methods were then placed in a proposed CEC Program Alternative Methods Decision Tree in order to provide a project strategy overview (see Figure 4). The Decision Tree is a three- step process that will assign each CEC to one of seven chemical categories:
• Category A: CEC with unknown chemical structure • Category B1: Non-pharmaceutical CEC; Genotoxin/Carcinogen • Category B2: Non-pharmaceutical CEC; Non-genotoxin/Non-carcinogen • Category B3: Non-pharmaceutical CEC; Unknown Genotoxin/Carcinogen Status • Category C1: Pharmaceutical CEC; Genotoxin/Carcinogen • Category C2: Pharmaceutical CEC; Non-genotoxin/Non-carcinogen • Category C3: Pharmaceutical CEC; Unknown Genotoxin/Carcinogen Status
Each of the seven categories has its own unique complement of these alternative risk assessment methods from which the appropriate safe harbor criteria would be derived. Table ES-1 presents this listing of methods for each of the Decision Tree categories.
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Table ES-1: Listing of Alternative Risk Assessment Methods by Decision Tree Category Decision Tree Category Retained Method A Unidentified CEC Threshold of Toxicological Concern Approach Percentile Approach Non-pharmaceuticals B1 Genotoxins/Carcinogens Threshold of Toxicological Concern Approach Virtual Safe Dose Approach Percentile Approach B2 Non-genotoxins/non Threshold of Toxicological Concern Approach carcinogens LD50 Extrapolation Approach Percentile Approach B3 Genotoxicity/carcinogenicity QSAR/surrogate Approach undetermined Threshold of Toxicological Concern Approach Percentile Approach Pharmaceuticals C1 Genotoxins/carcinogens Threshold of Toxicological Concern Approach Virtual Safe Dose Approach Percentile Approach C2 Non-genotoxins/non Threshold of Toxicological Concern Approach carcinogens Lowest Therapeutic Dose Approach Percentile Approach C3 Genotoxicity/carcinogenicity QSAR/surrogate Approach undetermined Threshold of Toxicological Concern Approach Percentile Approach
There are two types of alternative methodologies that were discovered in this first phase of this project – ones yielding generic toxicological benchmarks and ones yielding chemical-specific toxicological benchmarks. A generic toxicological benchmark is a value that can be applied to many chemical compounds in contrast to a chemical-specific benchmark which is only applied to one CEC. Generic toxicological benchmarks generally do not require any, or little, contaminant-specific information for their derivation.
Generic Methods
Percentile Approach. The percentile approach is an alternative risk assessment method that utilizes the Minnesota health based guidance for drinking water database (comprised of HRL/HBV/RAA) to directly calculate a generic CEC advisory value. The database of HRL/HBV/RAA values, comprised of 197 entries (see Table 1) was generated after removing both metal/element values and MCL-based values from MDH’s complete HRL/HBV/RAA database. The reason why the metal values were eliminated was that none of the alternative methods that were being considered addressed metals or metal-containing compounds. The MCL-based values were
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eliminated because the methods used for their derivation differed from the MDH methods used for all other compounds.
This database was utilized in its entirety for this method, and it was subdivided into cancer-based HRL/HBV/RAA and non-cancer-based HRL/HBV/RAA. Lastly, the values in each of these three datasets were arranged according to magnitude, from smallest to largest. A value representing a specific percentile in each database was then chosen as a provisional generic CEC advisory value. An overall screening value of 0.002 µg/L (currently the lowest value in the MDH database) was proposed for an initial review step in assessing CECs. Subsequent to the initial review step the CEC would be categorized regarding genotoxicity/carcinogenicity. A value of 0.004 µg/L was selected for carcinogens (the 5th percentile value from this database). For non- carcinogens, the 5th percentile value of 1.0 µg/L was proposed. This method is applicable to all seven categories of CECs in the Decision Tree.
Threshold of Toxicological Concern. The threshold of toxicological concern (TTC) method is another alternative risk assessment method that generates generic toxicological benchmarks. It was first proposed and then later developed by FDA scientists to address indirect food additives. It is now used in Europe for a variety of other applications, such as impurities in pharmaceuticals.
As with the percentile approach, this generic method evaluates carcinogenic chemicals separately from non-carcinogenic chemicals. For carcinogens and genotoxins: • A dose of 0.0025 µg/kg-d is applied to chemicals containing certain ‘structural alerts’ • A dose of 0.025 µg/kg-d is applied to genotoxins not containing one of these structural alerts.
For non-carcinogens: • A dose of 0.3 µg/kg-d is applied to organophosphate (OP) compounds • A dose of 1.5 µg/kg-d is applied to Cramer class III compounds • A dose of 9.0 µg/kg-d is applied to Cramer class II compounds • A dose of 30.0 µg/kg-d is applied to Cramer class I compounds
This method, however, is not recommended for any aflatoxin-like (e.g., strained ring) compound, any steroid, azoxy or N-nitroso-containing chemical, any polymers, any endocrine disruptors, any particulate matter, any heavily halogenated ring chemicals, or any compound having a long biological half-life.
An analysis of the above published TTC values against the reference doses and 10-5 excess lifetime cancer risk doses embedded in MDH’s HRL/HBV/RAA database determined that: • The 0.025 µg/kg-d carcinogen without structural alerts TTC was lower in magnitude (i.e., protective) than 65% of the HRL/HBV/RAA 10-5 dose levels in
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this database. The 0.0025 µg/kg-d TTC for carcinogens with structural alerts was lower than 81% of the HRL/HBV/RAA 10-5 dose levels in this database. • The OPI TTC value of 0.3 µg/kg-d was protective of only 2 of 6 compounds in this database (33 %) • The Cramer class I value of 30.0 µg/kg-d was protective of 25 of 27 class I chemicals in the MDH database (93%) • The Cramer class II value of 9.0 µg/kg-d was protective of 2 of 3 class II chemicals in the MDH database (67%), and • The Cramer class III value of 1.5 µg/kg-d was protective of 101 of 113 class III chemicals in the MDH database (89%)
It was noted in a comparative analysis as part of this project that the HRL/HBV/RAA database contains a much higher percentage of halogenated chemicals (80%) than either a published database of pharmaceuticals (14%), a database of personal and household care products (7%), or a database of cosmetic ingredients (4%). It is possible that MDH’s HRL/HBV/RAA database is not representative toxicologically of the CEC database and more likely than not comprised of more potent chemicals. Thus, the TTC values published by various investigators and itemized above were recommended as provisional advisory values to the CEC Program.
These TTC values can be converted into water quality criteria using existing MDH algorithms. Such an analysis was performed and showed similar chemical capture with the exception of Class I, which exhibited a lower capture efficiency.
This method does have some chemical restrictions in its application as noted previously, but it still could be applied to all seven categories of CEC in the Decision Tree.
Chemical-specific Methods
Lowest Therapeutic Dose Approach. The lowest therapeutic dose (LTD) approach is a procedure that is designed specifically and exclusively for pharmaceuticals. Two forms of this approach exist and were evaluated in this project – a simplistic form and a refined form. Both forms utilize the same basic algorithm:
Reference Dose (mg/kg-d) = LTD (mg/kg-d)/UF
where: UF = a composite uncertainty factor
In the simplistic approach, generic UF are used. For example, in California, the UF is:
• 1000, if a NOAEL is established for a drug and the compound is not an endocrine disruptor • 3000, if the LTD is used for a drug and the compound is not an endocrine disruptor
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• 30,000, if the LTD is used for a drug and the compound is either a non-genotoxic carcinogen or an endocrine disruptor.
Other entities, such as the National Water Quality Management Strategy of Australia and the WateReuse Foundation in the US have their own sets of generic UF that differ from those of California. The California UF values have been suggested to the CEC Program for the development of provisional advisory values.
In the refined approach, a pharmaceutical-specific UF is generated by evaluating five individual attributes of the underlying database for each chemical:
• LOAEL-to-NOAEL extrapolation (assumption is made that LTD = LOAEL) • Exposure Duration • Interspecies Variability • Inter-individual susceptibility • Data Quality
Since this latter refined approach is labor intensive (basically the same as the traditional US EPA reference dose calculation), it is viewed as most useful for HRL development for pharmaceuticals. Regardless of the approach used, a reference dose calculated in this manner can be converted into a water quality criterion using MDH algorithms.
LD50 Extrapolation Approach. The LD50 extrapolation approach utilizes an extrapolation factor to calculate a chronic NOAEL for a chemical from its published LD50 value. This method is only applicable to non-carcinogens/non-genotoxins (Categories B2 and C2 in the Decision Tree). The NOAEL derived by this method can then be converted into an RfD that can be subsequently used to derive a water quality criterion using MDH algorithms.
The extrapolation factor is derived from an underlying database of chemicals. For this exercise, the 95th percentile extrapolation factor of 10,000 that was published by Kramer et al. (1996) is suggested for the CEC Program. A CEC-specific chronic NOAEL is therefore calculated as:
Chronic NOAEL (mg/kg-d) = Lowest Mammalian LD50/10,000
When this method was applied to the HRL/HBV/RAA database, the method was able to capture 95-98% of the non-carcinogenic NOAELs in the database, depending on whether the lowest published mammalian LD50 was used or the mean LD50 was used.
Virtual Safe Dose. The virtual safe dose (VSD) approach is another chemical- specific extrapolation factor method, only this method is designed exclusively for carcinogens/genotoxins. In this method, an extrapolation factor is applied to a maximum tolerated dose (which is obtained from a subchronic oral exposure study) in
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order to derive an exposure dose equating to an incremental increase in lifetime cancer risk (e.g., 1 in 100,000). This method was originally developed by Gaylor (1989) to assist the NCI/NTP in prioritizing chemical substances for long-term animal bioassay testing. Using a database of over 300 chemicals, Gaylor and Gold reported a 95th percentile extrapolation factor of 5,770,000 to obtain a VSD equating to a 10-6 risk level. Their geometric mean extrapolation factor was 942,000. Conversion of these extrapolation factors to a 10-5 risk level yields values of 94,200 and 577,000. Application of these factors to the toxicological data embedded in MDH’s HRL/HBV/RAA database determined that neither extrapolation factor captured even a majority of the chemicals. As discussed above, it is possible that the HRL/HBV/RAA database is not representative of a CEC database and more likely than not to be comprised of more potent chemicals. Therefore, it is currently unknown if these extrapolation factors are appropriate for the CEC Program.
Surrogate Approach. The classical surrogate chemical approach is a method in which one chemical with known toxicological properties is used to represent a second chemical, usually of similar structure, but with insufficient information regarding toxicological properties. This approach has most recently been formalized by the EU in what is termed the “read-across” approach. In the read-across approach, a group of chemicals is evaluated for the purpose of selecting the best chemical surrogate from the group for the target chemical. This group concept was extended further in this project in that the chemical group members are used to decide each individual toxicological characteristic for a target chemical. Thus, the final outcome of this latest type of a toxicity assessment is not a single chemical surrogate but rather a toxicological composite from the group. Since this methodology is both a time- and a resource-intensive effort, it is being suggested as most useful in the development of HRL/HBVs by MDH and for filling-in data gaps in the HRL/HBV analysis.
The final outcome from these first two phases of this project is a set of alternative risk assessment methods that in total will be able to maximize the ability of MDH to provide health-based guidance to the public and to Minnesota regulators for CEC, while minimizing situations in which such guidance cannot be given. As noted previously, none of these methods address metals/elements, particulate matter, and polymers. Metals/elements possess toxicological information, so when these contaminants need to be addressed by the CEC Program, they can be evaluated with current MDH methods. The other contaminant types that are not being addressed with these alternative methods likely comprise only a small portion of the CEC database. These substances will have to be addressed on a case-by-case basis.
The last phase of this project will be the application of the above provisional alternative risk assessment methods to specific CEC compounds in a blind study in order to obtain additional insights as to their usefulness to the Program, as well as to refine and/or finalize the quantitative aspects of each of the selected methods.
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Table of Contents Page
Title Page …………………………………………………………………………… 1
Abbreviations and Acronyms ………………………………………………………. 2
Executive Summary ………………………………………………………………… 6
Table of Contents …………………………………………………………………… 13
Chapter 1: Project Introduction ……………………………………………………. 17
Chapter 2: A Decision Tree Strategy for MDH’s CEC Program…………………… 20 2.1 Background ………………………………………………………………… 20 2.2 Decision Tree ………………………………………………………………. 21 2.3 Genotoxin/Carcinogen Designation Analysis ……………………………….. 23 2.4 Introduction to the Ten Alternative Risk Assessment Methods …………… 24 2.4.1 As Low As Reasonably Achievable Approach (ALARA) ………………… 24 2.4.2 LD50 Extrapolation Approach (LD50) ……………………………………. 24 2.4.3 Margin of Exposure Approach (MOE) …………………………………….. 25 2.4.4 Lowest Therapeutic Dose Approach (LTD)………………………………… 25 2.4.5 Percent Sample Mass Approach (% Mass) …………………………………. 26 2.4.6 Percentile Approach (% ile) …………………………………………………. 26 2.4.7 Quantitative/Qualitative Structure Activity Relationships (QSAR) ………... 26 2.4.8 Surrogate Compound Approach (Surrogate) ………………………………... 27 2.4.9 Threshold of Toxicological Concern Approach (TTC) ……………………... 28 2.4.10 Virtual Safe Dose Approach (VSD) ………………………………………… 29
Chapter 3: Alternative Risk Assessment Methods. Analyses of the Initial Ten Candidate Procedures ……………………………………………………………………………. 30 3.1 ALARA Approach ………………………………………………………………. 30 3.1.1 Method Description …………………………………………………………… 30 3.1.2 Method Background …………………………………………………………... 30 3.1.3 Method Application and Analysis …………………………………………….. 31 3.1.4 Method Critique ………………………………………………………………. 31 3.1.5 Recommendation ……………………………………………………………… 32 3.2 LD50 Extrapolation Approach …………………………………………………… 32 3.2.1 Method Description …………………………………………………………… 32 3.2.2 Method Background ………………………………………………………….. 32 3.2.3 Method Application and Analysis ……………………………………………. 33 3.2.4 Method Critique ………………………………………………………………. 37 3.2.5 Recommendation ……………………………………………………………… 38 3.3 Margin of Exposure Approach …………………………………………………… 39 3.3.1 Method Description …………………………………………………………… 39
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3.3.2 Method Background …………………………………………………………… 39 3.3.3 Method Application and Analysis …………………………………………….. 40 3.3.4 Method Critique ……………………………………………………………….. 40 3.3.5 Recommendation ………………………………………………………………. 41 3.4 Lowest Therapeutic Dose Approach ……………………………………………… 41 3.4.1 Method Description ……………………………………………………………. 41 3.4.2 Method Background …………………………………………………………… 42 3.4.3 Method Application and Analysis …………………………………………….. 47 3.4.4 Method Critique ……………………………………………………………….. 50 3.4.5 Recommendation ………………………………………………………………. 51 3.5 Percent Sample Mass Approach ………………………...... 51 3.5.1 Method Description …………………………………………………………….. 51 3.5.2 Method Background ……………………………………………………………. 51 3.5.3 Method Application and Analysis ……………………………………………… 51 3.5.4 Method Critique ………………………………………………………………… 52 3.5.5 Recommendation ……………………………………………………………….. 52 3.6 Percentile Approach ………………………………………………………………. 52 3.6.1 Method Description …………………………………………………………….. 52 3.6.2 Method Background ……………………………………………………………. 53 3.6.3 Method Application and Analysis ……………………………………………… 53 3.6.4 Method Critique ………………………………………………………………… 54 3.6.5 Recommendation ……………………………………………………………….. 58 3.7 In Silico Methods …………………………………………………………………. 58 3.7.1 Method Description/Background – QSAR …………………………………….. 58 3.7.2 Method Description/Background -- ToxCastTM ………………………………… 59 3.7.3 Method Application and Analysis ……………………………………………… 60 3.7.4 Method Critique ………………………………………………………………… 60 3.7.5 Recommendation ……………………………………………………………….. 61 3.8 Surrogate Approach ………………………………………………………………. 62 3.8.1 Method Description …………………………………………………………….. 62 3.8.2 Method Background ……………………………………………………………. 64 3.8.3 Method Application and Analysis ……………………………………………… 64 3.8.4 Method Critique ………………………………………………………………… 71 3.8.5 Recommendation ……………………………………………………………….. 71 3.9 Threshold of Toxicological Concern Approach ………………………………….. 72 3.9.1 Method Description …………………………………………………………….. 72 3.9.2 Method Background ……………………………………………………………. 72 3.9.3 Method Application and Analysis ……………………………………………… 78 3.9.4 Method Critique ………………………………………………………………... 82 3.9.5 Recommendation ………………………………………………………………. 83 3.10 Virtual Safe Dose Approach ……………………………………………………. 85 3.10.1 Method Description ……………………………………………………………. 85 3.10.2 Method Background …………………………………………………………… 85 3.10.3 Method Application and Analysis …………………………………………….. 86 3.10.4 Method Critique ……………………………………………………………….. 89 3.10.5 Recommendations ……………………………………………………………… 90
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Chapter 4: Application of the Retained Alternative Risk Assessment Methods in the Decision Tree ………………………………………………………….……………… 91
4.1 Category A: Unidentified Chemicals …………………………………………… 91 4.2 Category B1: Genotoxic/Carcinogenic Non-pharmaceuticals ………………….. 92 4.3 Category B2: Non-genotoxic/Non-carcinogenic Non-pharmaceuticals …………93 4.4 Category B3: Non-pharmaceuticals with Undetermined Status as to Genotoxicity/Carcinogenicity ………………………………………………….... 94 4.5 Category C1: Genotoxic/Carcinogenic Pharmaceuticals ……………………….. 94 4.6 Category C2: Non-genotoxic/Non-carcinogenic Pharmaceuticals ………………95 4.7 Category C3: Pharmaceuticals with Undetermined Status as to Genotoxicity/Carcinogenicity …………………………………………………… 96
Chapter 5: References ………………………………………………………………... 97
Figures (presented following text)
1. Decision Tree Strategy – Initial Proposal 2. Analog Group Approach 3. Kroes et al. 2004 TTC Decision Tree 4. Decision Tree Strategy – Final Proposal
List of Tables (presented following figures)
MDH Table 1: MDH Drinking Water Guidance Value Database (minus metals and MCLs) MDH Table 2A: LD50 Approach – Lowest LD50, 95th % EF, Chronic NOAEL Comparisons MDH Table 2B: LD50 Approach - Mean LD50, 95th % EF, Chronic NOAEL Comparisons MDH Table 2C: LD50 Approach – Lowest LD50, 95 UCL of 95th % EF, Chronic NOAEL Comparisons MDH Table 2D: LD50 Approach – Mean LD50, 95 UCL of 95th % EF, Chronic NOAEL Comparisons MDH Table 3A: LD50 Approach – Lowest LD50, 95th % EF, Water Quality Guidance Value Comparisons MDH Table 3B: LD50 Approach – Mean LD50, 95th % EF, Water Quality Guidance Value Comparisons MDH Table 3C: LD50 Approach – Lowest LD50, 95 UCL of 95th % EF, Water Quality Guidance Value Comparisons MDH Table 3D: LD50 Approach – Mean LD50, 95 UCL of 95th % EF, Water Quality Guidance Value Comparisons MDH Table 4: Percentile Approach – MDH Non-cancer Chronic HRL/HBV/RAA Database MDH Table 5: Percentile Approach – MDH Cancer HRL/HBV/RAA Database
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MDH Table 6: TTC Approach – MDH Cancer HRL/HBV/RAA Database MDH Table 6a: TTC Approach – MDH Cancer HRL/HBV/RAA Database (exempted chemicals removed) MDH Table 7: TTC Approach – MDH Non-cancer Chronic HRL/HBV/RAA Database MDH Table 7a: TTC Approach – MDH Cholinesterase Inhibition HRL/HBV/RAA Database MDH Table 7b: TTC Approach – MDH Non-cancer Chronic HRL/HBV/RAA Database (exempted chemicals removed); Segregated by Cramer Classification MDH Table 8: TTC Approach – MDH Cancer HRL/HBV/RAA Database (exempted chemicals removed) MDH Table 9: TTC Approach – MDH Cholinesterase Inhibition HRL/HBV/RAA Database MDH Table 10: TTC Approach – MDH Non-cancer HRL/HBV/RAA Database (exempted chemicals removed), Segregated by Cramer Classification MDH Table 11: VSD Approach – Mean MTD/VSD EF, Dose Comparisons MDH Table 12: VSD Approach – 95th Percentile MTD/VSD EF, Dose Comparisons MDH Table 13: VSD Approach – Mean MTD/VSD EF, Water Quality Guidance Value Comparisons MDH Table 14: VSD Approach – 95th Percentile MTD/VSD EF, Water Quality Guidance Value Comparisons
APPENDIX A: Genotoxicity Test Hierarchy for Classifying Contaminants as Potential Genotoxic Carcinogens.
APPENDIX B: List and Brief Description of QSAR Programs
APPENDIX C: US EPA HPV Chemical Grouping Database
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