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
ADI
Acceptable Daily Intake
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
2
[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.]
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
3
[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.]
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
4
[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.]
US EPA
US Environmental Protection Agency
WHO
World Health Organization
WRF
WateReuse Research Foundation
VSD
Virtual Safe Dose
5
[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.]
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
6
[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.]
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 threestep process that will assign each CEC to one of seven chemical categories:
•
•
•
•
•
•
•
Category A:
Category B1:
Category B2:
Category B3:
Category C1:
Category C2:
Category C3:
CEC with unknown chemical structure
Non-pharmaceutical CEC; Genotoxin/Carcinogen
Non-pharmaceutical CEC; Non-genotoxin/Non-carcinogen
Non-pharmaceutical CEC; Unknown Genotoxin/Carcinogen Status
Pharmaceutical CEC; Genotoxin/Carcinogen
Pharmaceutical CEC; Non-genotoxin/Non-carcinogen
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.
7
[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.]
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
8
[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.]
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 noncarcinogens, 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
9
[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.]
•
•
•
•
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
10
[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.]
• 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 chemicalspecific 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
11
[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.]
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.
12
[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.]
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……………………
2.1 Background …………………………………………………………………
2.2 Decision Tree ……………………………………………………………….
2.3 Genotoxin/Carcinogen Designation Analysis ………………………………..
2.4 Introduction to the Ten Alternative Risk Assessment Methods ……………
2.4.1 As Low As Reasonably Achievable Approach (ALARA) …………………
2.4.2 LD50 Extrapolation Approach (LD50) …………………………………….
2.4.3 Margin of Exposure Approach (MOE) ……………………………………..
2.4.4 Lowest Therapeutic Dose Approach (LTD)…………………………………
2.4.5 Percent Sample Mass Approach (% Mass) ………………………………….
2.4.6 Percentile Approach (% ile) ………………………………………………….
2.4.7 Quantitative/Qualitative Structure Activity Relationships (QSAR) ………...
2.4.8 Surrogate Compound Approach (Surrogate) ………………………………...
2.4.9 Threshold of Toxicological Concern Approach (TTC) ……………………...
2.4.10 Virtual Safe Dose Approach (VSD) …………………………………………
20
20
21
23
24
24
24
25
25
26
26
26
27
28
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
13
[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.]
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
14
[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.]
Chapter 4: Application of the Retained Alternative Risk Assessment Methods in the
Decision Tree ………………………………………………………….……………… 91
4.1
4.2
4.3
4.4
Category A: Unidentified Chemicals …………………………………………… 91
Category B1: Genotoxic/Carcinogenic Non-pharmaceuticals ………………….. 92
Category B2: Non-genotoxic/Non-carcinogenic Non-pharmaceuticals …………93
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.
2.
3.
4.
Decision Tree Strategy – Initial Proposal
Analog Group Approach
Kroes et al. 2004 TTC Decision Tree
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
15
[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.]
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
16
[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.]