Six-Year Review

    Chemical
  Contaminants

  Health Effects
Technical Support
    Document

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Office of Water
Office of Science and Technology
EPA 822-R-03-008
June 2003
                                          Printed on Recycled Paper

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                                         EPA 822-R-03-008
          Six-Year Review

      Chemical Contaminants

           Health Effects

    Technical Support Document


               June 2003
United States Environmental Protection Agency
             Office of Water
      Office of Science and Technology
   Health and Ecological Criteria Division
   1200 Pennsylvania Avenue, NW (4304 T)
         Washington, D.C. 20460
                  11

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Ill

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                                   CONTENTS

Abbreviations  	v

1.  INTRODUCTION	1

2.  MAXIMUM CONTAMINANT LEVEL GOAL	1
   2.1.   Reference Dose  	1
   2.2.   Assessment of Carcinogenicity 	2

3.  IDENTIFYING CANDIDATES FOR POSSIBLE REGULATORY REVISION  	3

4.  NOMINATION OF CHEMICALS FOR NEW RISK ASSESSMENT  	4
   4.1.   Priority Chemicals of Potential Reproductive/Developmental Concern	5
   4.2.   Other Nominations for New Risk Assessment  	7

5.  SUMMARY	9

Table 1.  Cancer classification systems used by EPA  	10

Table 2.  Chemicals considered under the first Six-Year Review cycle  	11

Table 3.  Assessment by IRIS, OPP, ATSDR, and NAS of chemicals considered under the first
   Six-Year Review cycle	18

Table 4.  Evaluation of the literature search for reproductive and developmental toxicity	23

Table 5.  Overall review of chemicals	25

REFERENCES 	30
                                       IV

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Abbreviations

ATSDR       Agency for Toxic Substances and Disease Registry
BMD         Benchmark dose
bw           Body weight
CCRIS        Chemical Carcinogenesis Research Information System
DART        Developmental and Reproductive Toxicology
DEHA        Di(2-ethylhexyl)adipate
EC           European Commission
EPA          U.S. Environmental Protection Agency
FQPA         Food Quality Protection Act
HSDB        Hazardous Substances Data Bank
I             Daily drinking water intake
IARC         International Agency for Research on Cancer
IRIS          Integrated Risk Information System
kg            Kilogram
LOAEL       Lowest-observed-adverse-effect level
MCL         Maximum contaminant level
MCLG        Maximum contaminant level goal
MF           Modifying factor
MFL         Million fibers per liter
mg           Milligram
MRL         Minimal risk level
NA           Not available
NAS         National Academy of Sciences
NDWAC      National Drinking Water Advisory Council
NIEHS        National Institute of Environmental Health Sciences
NOAEL       No-observed-adverse-effect level
NPDWR      National Primary Drinking Water Regulation
NTP          National Toxicology Program
OPP          Office of Pesticide Programs
OST          Office of Science and Technology
OW          Office of Water
RfD          Reference dose
RSC          Relative source contribution
SDWA        Safe Drinking Water Act
TT           Treatment technology
UF           Uncertainty  factor
UL           Tolerable upper intake level
WHO         World Health Organization

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1.   INTRODUCTION

     The Environmental Protection Agency (EPA) has developed a Protocol for the Review of
Existing National Primary Drinking Water Regulations (USEPA, 2003 a) based on
recommendations of the National Drinking Water Advisory Council (NDWAC, 2000), through
consultations with stakeholders representing a wide variety of interest groups, and internal
Agency deliberations. The Protocol outlines the approach to be used to review and identify
national primary drinking water regulations (NPDWRs) that warrant revision to maintain, or
provide for greater, public health protection.  The key elements of the review process are health
effects, analytical and treatment technology, other regulatory revisions (e.g., monitoring and
reporting requirements), occurrence and exposure analysis and, as appropriate, economic
considerations.

     The purpose of the health effects component of the review process is to identify, within the
limitations of the Agency's available resources, new health risk assessments that indicate
possible change to the maximum contaminant level goal (MCLG) and, perhaps, to the maximum
contaminant level (MCL).

     A total of 68 regulated chemical contaminants are being considered during this first Six-
Year Review cycle.  These are inorganic and organic contaminants regulated prior to the Safe
Drinking Water Act (SDWA) 1996 Amendments, except arsenic, radionuclides, disinfectant
residuals, and disinfection by-products, which are being or have already been reviewed in
separate actions.

2.   MAXIMUM CONTAMINANT LEVEL GOAL

     Because the identification of contaminants for potential revision based on health effects is
dependent on whether or not the MCLG could change, a brief explanation of the derivation of
the MCLG is warranted. The MCLG is the maximum level of a contaminant in drinking water at
which no known or anticipated adverse health effects occur, allowing for an adequate margin of
safety.  MCLGs are non-enforceable health goals.  EPA establishes the MCL based on the
MCLG.  The MCL is the maximum permissible level of a contaminant in water that is delivered
to any user of a public water system.  Prior to the 1996 Amendments to the SDWA, the MCL
was set as close to the MCLG as was feasible.  The 1996 Amendments to the SDWA permit
consideration of costs and benefits in establishing an MCL. MCLs are enforceable standards.

2.1.  Reference Dose

     For chemicals exhibiting a threshold for toxic effects, EPA establishes the MCLG on the
basis of an oral reference dose (RfD). A change in the RfD could lead to a change in the MCLG
and thus in the MCL. The RfD is an estimate (with uncertainty spanning perhaps an order of
magnitude) of a daily oral exposure to the human population (including sensitive subgroups) that
is likely to be without an appreciable risk of deleterious noncancer effects during a lifetime. The
RfD is derived as follows:

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                     RfD (mg/kg/day)  =  NOAEL or LOAEL or BMP
                                               UF xMF
where:
       NOAEL     =    no-observed-adverse-effect level (mg/kg/day)
       LOAEL     =    lowest-observed-adverse-effect level (mg/kg/day)
       BMD       =    benchmark dose (mg/kg/day)
       UF          =    uncertainty factor
       MF         =    modifying factor

The UF is used to account for the extrapolation uncertainties (e.g., interindividual variation,
interspecies differences, duration of exposure, use of a LOAEL in place of a NOAEL), and
database adequacy. The MF is used as a judgment factor to account for the confidence in the
critical study (or studies) used in the derivation of the RfD (USEPA, 2000).

     The MCLG is then derived from the RfD as follows:

                          MCLG (mg/liter)  =  RfD x bw x RSC
                                                     I

where:
       bw     =   body weight (70 kg for adults, 10 kg for children, 4 kg for infants);
       RSC   =   relative source contribution, the fraction of the RfD allocated to drinking
                   water (to take into account exposure from other sources);
       I      =   daily drinking water intake (2 liters for adults, 1 liter for children, 0.64 liter
                   for infants).

     EPA generally assumes that the relative source contribution from drinking water is 20
percent of the RfD, unless other exposure data for the chemical are available.  This allows 80
percent of the total exposure to come from sources other than drinking water, such as exposure
from food, inhalation, or dermal contact.  The RSC is one factor that will determine whether or
not a change in the RfD will lead to a change in the MCLG.

     It has also been the Agency policy to apply an additional safety factor to the RfD for
chemicals with limited evidence of carcinogenicity (Section 2.2).  This practice is another factor
that must be evaluated to determine the impact of a change in RfD on the MCLG.

2.2.  Assessment of Carcinogenicity

     For drinking water contaminants regulated prior to the 1996 SDWA, OW followed a three-
category regulatory cancer classification system (Categories I, II, or III). These categories
specify decisions as to degree of concern for an agent's carcinogenic potential as a contaminant
of drinking water, and define to some extent the approach to risk management that is taken for
establishing MCLGs. Categories I,  II, and III are designations not defined in guidelines but that
reflect Office of Water (OW) policy.

     EPA also used the  six alphanumeric categories (A, Bl, B2, C, D, E) of the 1986 cancer
guidelines (USEPA, 1986) in establishing the MCLG.  The six-group classification system is
often equated to the three-category system in the NPDWR Federal Register announcements.
Table 1 describes the three categories and, with few exceptions (e.g., beryllium), their usual

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equivalent alphanumeric classification. If a chemical is a known or probable human carcinogen
(Category I, generally Group A or B), the MCLG is generally set at zero because it is assumed,
in the absence of other data, that there is no known threshold for carcinogenicity. If a chemical
falls in Group C, a RfD approach along with an additional safety factor is used in deriving the
MCLG. The methodology used for establishing MCLGs for chemicals with varying degrees of
evidence of carcinogenicity is briefly described in Table 1.

    Recent Agency assessments also use the 1996 Proposed Guidelines for Carcinogen Risk
Assessment (USEPA, 1996) or the draft revised Guidelines for Carcinogen Risk Assessment
(USEPA, 1999).  The proposed and revised Guidelines use standard descriptors as part of the
hazard narrative to express the weight of evidence for carcinogenic hazard potential.  These
hazard descriptors are given in the text whenever appropriate.

3.  IDENTIFYING CANDIDATES FOR POSSIBLE REGULATORY REVISION

    EPA will identify regulated chemical contaminants for which there have been changes in
the RfD and/or in cancer risk assessment from oral exposure.  Such changes could result in a
change in the MCLG and MCL. Chemicals thus identified are potential candidates for
regulatory revision.

    Health risk assessments completed under the following programs will be examined:

    EPA Integrated Risk Information System (IRIS)
    EPA Office of Pesticide Programs (OPP)
•   National Academy of Sciences (NAS)
•   Agency  for Toxic Substances and Disease Registry (ATSDR)

    Table 2 lists the 68 chemicals included in the Six-Year Review process, the RfDs and
cancer groups on which the MCLGs are based, those established by IRIS and OPP, and
assessment dates. The uses of certain pesticides are currently "banned" or "severely restricted."
These pesticides  are indicated as "canceled" under OPP columns. Updated risk assessments of
canceled pesticides are usually done by EPA's offices other than OPP. IRIS dates are difficult to
determine with any precision because of numerous sequential revisions described in the
"Revision History" for each substance. Dates of IRIS assessments are approximate and refer to
the most recent year when significant revisions were made to the RfD or cancer assessment. Risk
assessments conducted by IRIS and OPP can be found at www.epa.gov/iris/index.html and
www.epa.gov/pesticides/reregistration/status.htm, respectively.

    IRIS and OPP do not use the three-category approach for cancer hazard characterization,
but use the  1986  Guidelines for carcinogen risk assessment and, recently, the 1996  and 1999
proposed cancer Guidelines (USEPA, 1986; USEPA, 1996; USEPA, 1999). For easy
comparison, Categories I, II, and III on which the MCLGs are based have been replaced by the
equivalent cancer groups of the 1986 cancer guidelines (Table 1). If the oral  and inhalation
cancer groups differ, the cancer groups given in Table 2 are those for oral exposure. Whenever
appropriate, the cancer hazard  descriptors of the 1996 or 1999 proposed cancer Guidelines  are
also given in Table 2.

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     As indicated in Table 2, NAS established in 1997 a tolerable upper intake level (UL) for
fluoride of 10 mg/day for children older than eight years and for adults, based on protection
against skeletal fluorosis (NAS, 1997). The 1997 NAS evaluation of fluoride does not have an
impact on the MCLG. In addition, recent assessments of copper and selenium by NAS (NAS,
2000a; NAS, 2000b) do not have an impact on the MCLGs for these two chemicals.

     ATSDR establishes oral minimal risk levels (MRLs) for non-neoplastic endpoints for acute,
intermediate, and chronic exposure durations. MRLs for oral chronic exposure are similar to
EPA's RfDs.  The chronic MRL for cadmium of 1999 is the only one among the chemicals under
consideration that is more recent than and different from the RfD established in 1991.  As such,
cadmium would qualify for possible revision. However, a new IRIS assessment of cadmium is
due in 2003 or 2004 (Table 3). Further review and revision of cadmium is therefore not
appropriate until completion of the Agency's ongoing assessment.  In summary,  ATSDR
completed assessments do not have an impact on the selection of chemicals for potential revision
during this first Six-Year Review cycle.

     Nine chemicals given in bold in Table 2 potentially qualify for revision, because  of
different RfD and/or cancer assessments  postdating the MCLG. These are alachlor, beryllium,
chromium, 1,1-dichloroethylene, diquat,  glyphosate, lindane, oxamyl and picloram. However, as
of December 31, 2002, updated assessments for alachlor (IRIS), diquat (OPP), and glyphosate
(IRIS) are expected in 2003 or 2004 (Table 3). In addition, the National Toxicology Program
has initiated subchronic and  chronic toxicity studies for hexavalent chromium (NTP, 2002).
Therefore, further review and assessment of these four chemicals is not appropriate until
completion of the Agency's ongoing assessments, and NTP studies. The remaining five
chemicals are potential candidates for revision and are listed below together with the latest
assessment date.

              Beryllium (IRIS  1998)                Oxamyl (OPP 2000)
              1,1 -Dichloroethylene (IRIS 2002)      Picloram (OPP 1998)
              Lindane (OPP 2002)

     This tentative identification of chemicals potentially qualifying for revision was conducted
independently of other considerations (e.g., analytical and treatment technology, occurrence
data), which may influence the final selection of contaminants to be revised.

     For some chemicals with an MCLG of zero (chlordane, vinyl chloride), a change in RfD
postdating the regulation occurred in 1998 or later without a change in cancer group.  These
chemicals do not potentially qualify for revision because,  following Agency policy, the MCLG
for these chemicals will remain at zero, irrespective of any change in RfD.

4.   NOMINATION OF CHEMICALS FOR NEW RISK ASSESSMENT

     In order to identify chemicals for which current risk  assessments need updating, the Office
of Science and Technology conducted a full toxicological literature search, including
developmental and reproductive toxicity, for a number of chemicals with current risk
assessments conducted prior to 1997. The toxicological literature search included at a minimum
the following databases: TOXLINE, MEDLINE, Developmental and Reproductive Toxicology
(DART), Chemical  Carcinogenesis Research Information  System (CCRIS), NTP, and Hazardous

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Substances Data Bank (HSDB).  In addition, recent risk assessments conducted by several
national and international institutions were also examined for toxicological information. These
organizations/institutions included the World Health Organization (WHO), the International
Agency for Research on Cancer (IARC), the European Commission, Health Canada, California
Environmental Protection Agency, ATSDR, NAS and NIEHS.

4.1.  Priority Chemicals of Potential Reproductive/Developmental Concern

     With the passage of the 1996 SDWA Amendments and FQPA of 1996, a concerted effort
was made by EPA to take into account reproductive and developmental effects, and effects of
chemicals on sensitive subpopulations. However, contaminants under consideration in this first
Six-Year Review cycle were regulated in 1992 or earlier and might not have received adequate
scrutiny for reproductive and developmental effects. Accordingly, a literature search was
conducted by EPA's Office of Science and Technology (OST) to identify contaminants for
which developmental and/or reproductive effects might now appear to be the critical effects1.
Contaminants thus identified will be nominated as high priority for new Agency assessments.

     New assessments by IRIS or OPP are ongoing for several chemicals included in this first
Six-Year Review cycle.  Any reproductive or developmental effects of these chemicals will be
taken fully into consideration as part of these new assessments.  Therefore, a literature search for
reproductive/developmental effects was not considered useful for the 31 chemicals listed below
with ongoing IRIS (USEPA, 2002; USEPA, 2003b) or OPP assessments, as of December 31,
2002. Expected completion years of these assessments are indicated below. If, upon completion
of these new assessments, it is determined that there is a potential  impact on the MCLQ the
chemicals in question will be considered candidates for possible revision in the next Six-Year
Review cycle, unless a compelling reason exists to accelerate the review of thatNPDWR.
       1 Critical effect is defined as the biologically significant adverse effect expected to occur at the lowest dose.

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Endothall (OPP, 2003/2004)
Ethylbenzene (IRIS, 2003/2004)
Ethylene dibromide (IRIS, 2003/2004)
Glyphosate (IRIS, 2003/2004)
Methoxychlor (OPP, 2003)
Pentachlorophenol (IRIS, 2003/2004)
Polychlorinated biphenyls (IRIS, 2003/2004)
Simazine (OPP, 2003/2004)
Styrene (IRIS, 2003/2004)
2,3,7,8-TCDD (IRIS, 2003/2004)
Tetrachloroethylene (IRIS, 2003/2004)
Toluene (IRIS, 2003/2004)
1,1,1-Trichloroethane (IRIS, 2003/2004)
Trichloroethylene (IRIS, 2003/2004)
Xylenes (IRIS, 2003/2004)
 Acrylamide (IRIS, 2003/2004)
 Alachlor (IRIS, 2003/2004)
 Antimony (IRIS, 2003/2004)
 Asbestos (IRIS, 2005)
 Atrazine (OPP, 2003) *
 Benzo[a]pyrene (IRIS, 2003/2004)
 Cadmium (IRIS, 2003/2004)
 Carbofuran (OPP, 2003/2004)
 Carbon tetrachloride (IRIS, 2003/2004)
 Copper (IRIS, 2003/2004)
 2,4-D (OPP, 2004)
 Di(2-ethylhexyl)phthalate (IRIS, 2003/2004)
 1,2-Dichlorobenzene (IRIS, 2003/2004)
 1,4-Dichlorobenzene (IRIS, 2003/2004)
 1,2-Dichloroethane (IRIS, 2003/2004)
 Diquat (OPP,  2003)
     * Amended OPP Interim Reregistration Eligibility Decision (IRED) scheduled for release October 2003

     Twelve chemicals are not under review by IRIS or OPP but have an MCLG of zero. These
are listed below, together with the year of the most recent Agency cancer assessments (see also
Table 2).

 Benzene (00)                      1,2-Dichloropropane (91)   Hexachlorobenzene (92)
 Chlordane (98)                     Epichlorohydrin (92)       Lead (91)
 l,2-Dibromo-3-chloropropane (91)   Heptachlor (92)           Toxaphene (91)
 Dichloromethane (92)               Heptachlor epoxide (92)    Vinyl chloride (00)

     For these chemicals, an MCLG of zero will remain at zero, irrespective of new information
on reproductive or developmental effects, unless new information indicates that the
dose-response relationship for tumorigenesis is nonlinear. EPA reviewed recent IRIS, ATSDR
and IARC carcinogenicity assessments for these 12 chemicals to determine whether these
assessments may now indicate a mode of action that implies nonlinearity of the dose-response, in
which case an MCLG of zero would no longer be appropriate and might be based instead on
threshold effects  such as reproductive or developmental effects.  EPA did not find any data to
support such a nonlinear mode of action (IARC,  1999; IARC, 2001; ATSDR, 1999). Therefore,
revision of the MCLG of zero for these 12 chemicals is not appropriate at this time.

     Information on potential reproductive and developmental effects for chemicals with
MCLGs of zero may have an impact on risk management strategies, such as monitoring
frequency, to control peak occurrence. This aspect of the assessment will be considered during
subsequent Six-Year Review cycles, in conjunction with available occurrence data, to determine
whether changes in risk management strategies might provide for better public health protection.

     For chemicals with nonzero MCLGs, evaluation of the literature search for reproductive
and developmental effects was not considered necessary if new Agency assessments were
finalized in 1997 or later.  These assessments are recent enough to have considered reproductive
and developmental toxicity as a part of the evaluation. Agency assessments finalized in 1997 or
later are available for nine chemicals. These are barium (1998), beryllium (1998), chromium

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(1998), 1,1-dichloroethylene (2002), hexachlorocyclopentadiene (2001), lindane (2002),
inorganic mercury (1997), oxamyl (2000), and picloram (1998).

     The literature search for reproductive and developmental effects for the remaining 16
chemicals listed in Table 4 was evaluated. For various reasons briefly described in Table 4,
RfDs for three chemicals—cyanide, di(2-ethylhexyl)adipate, thallium—could be affected by new
information on developmental and/or reproductive toxicity. The small number of chemicals thus
identified is not surprising, as EPA's selection of contaminants for new IRIS or OPP assessment
is biased toward chemicals for which there is an indication that reproductive or developmental
effects may be of concern. In conclusion, three chemicals are high priority and, at the request of
OST, new IRIS risk assessments have been initiated for these chemicals. The new risk
assessments are expected to be completed in the 2005 time frame for cyanide, 2003/2004 for
di(2-ethylhexyl)adipate, and 2005 for thallium (USEPA, 2003b).

4.2.  Other Nominations for New Risk Assessment

     As described above, the literature search for reproductive and developmental effects for 16
chemicals was evaluated.  Three of these  chemicals were identified as  of potential reproductive
or developmental concern, and IRIS risk assessments were initiated in 2002. It was considered
desirable to determine, through a literature search for all other toxicological endpoints, if new
health effects information had become available for any of the remaining 13 chemicals, in which
case the chemical would be  nominated for a new assessment.

     Of the 13 chemicals under consideration, NAS conducted a recent assessment of selenium
and no new information was identified which may have an impact on the current MCLG (NAS,
2000b).  Therefore, selenium was eliminated from further consideration and a toxicological
literature search was conducted by OST for the remaining 12  chemicals. These are:
       Dalapon                     Endrin                 Nitrite
       cis-l,2-Dichloroethylene      Fluoride                2,4,5-TP (Silvex)
       trans-1,2-Dichloroethylene    Monochlorobenzene      1,2,4-Trichlorobenzene
       Dinoseb                     Nitrate                  1,1,2-Trichloroethane

     There is new information on the effects of fluoride on bone and on the contribution of
various sources to total fluoride exposure (dental health products, water, food, beverages)
(WHO,  2002). At the request of EPA, NAS has agreed to review the toxicological data on
fluoride for all toxicological endpoints, including effects on bone. NAS will also examine the
data on relative fluoride exposure from drinking water compared to fluoride exposure from the
diet and fluoride-containing dental products. It is anticipated that the NAS review will be
completed in  2004.

     No new  information was found for any of the remaining chemicals that could have an
impact on the MCLG. Accordingly, and for the time being, these contaminants will not be
nominated for new IRIS assessments.

     Because of considerable stakeholder interest in nitrate and nitrite, a more detailed rationale
for not considering these two chemicals as potential candidates for new IRIS assessments is
provided here. At the request of EPA, NAS evaluated the 1991 MCLGs and MCLs for nitrate
and nitrite. NAS evaluated the epidemiological and toxicological studies available for these

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chemicals and concluded that EPA's current MCLGs and MCLs for nitrate and nitrite are
adequate to protect human health.  NAS also concluded that exposure to nitrate/nitrite
concentrations found in drinking water in the United States is unlikely to contribute to human
cancer risk (NAS, 1995). In 1997, California established Public Health Goals for nitrate and
nitrite in drinking water identical to EPA's MCLGs and concluded that recent epidemiological
studies do not support an association between nitrate and nitrite exposure from drinking water
and increased cancer rates in humans (Cal/EPA, 1997). More recently,  the World Health
Organization (WHO) evaluated nitrate and nitrite and established the same "guideline values" for
these two chemicals as EPA's MCLGs, to protect against methemoglobinemia in bottle-fed
infants below three months of age, the most  susceptible segment of the population.  WHO also
concluded that there is no evidence for an association between  nitrite and nitrate exposure in
humans and the risk of cancer (WHO, 1998).

     A number of studies on nitrate and nitrite have become available since WHO's assessment
of 1998.  Some of these studies that could possibly have an impact on the MCLGs are discussed
here.  In an epidemiological study in Iowa, Weyer et al. (2001) found a positive relationship
between nitrate levels in drinking water and  risk of bladder and ovarian cancers, and an inverse
relationship  for cancer of the uterine corpus  and rectum.  The authors recognized that additional
studies were needed before confirming these trends.  Several limitations of the study were also
pointed out by the authors, including lack of information on individual water consumption and
poor characterization of the magnitude of exposure to nitrate, relatively small sample size for
bladder cancer, lack of information on occurrence of bladder infections, lack  of information on
concomitant exposure to other  contaminants in drinking water,  including disinfection by-
products. No clear and consistent associations were found between increasing nitrate in drinking
water and non-Hodgkin's lymphoma, leukemia, or cancers of the colon, breast, lung, pancreas,
or kidney (Weyer et al., 2001).  Other epidemiological studies of nitrate and/or nitrite and non-
Hodgkin's lymphoma (Ward et al., 1996), gastric, esophageal or brain cancer (Van Loon et al.,
1998, Barrett et al., 1998) are also inconclusive.  Several epidemiological studies  of maternal
ingestion of nitrate in drinking  water failed to confirm an association between nitrate exposure
and developmental effects in offspring (e.g., Croen et al., 1997).

     There are differing views  on the role of nitrate/nitrite versus gastrointestinal  infections as
the cause of infant methemoglobinemia (Avery, 1999; Knobeloch et al., 2000).  It is recognized
that bottle-fed infants have a high probability of developing gastrointestinal infections because of
their low gastric acidity.  It is also recognized that gastrointestinal infections and low acidity
enhance the  conversion of nitrate to nitrite and methemoglobin formation in infants.  This is an
additional reason for considering these infants as a high-risk group for developing
methemoglobinemia from  exposure to nitrate/nitrite (WHO, 1998).

     NTP carried out toxicology and carcinogenesis studies of sodium nitrite (NTP, 2001).
There was no evidence of carcinogenic activity of sodium nitrite in male or female rats, nor in
male mice.  There was equivocal evidence of carcinogenic activity in female  mice based on a
positive trend in the incidences of squamous cell papilloma or carcinoma (combined) of the
forestomach. Given these conclusions, a change in the cancer assessment of nitrite is not
warranted at this time.

     The outcome of the review of nitrate and nitrite indicates that the basis of the current
MCLGs for  these two chemicals remain appropriate and, therefore, nitrate and nitrite are not
nominated for new IRIS  assessments at this time.

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5.   SUMMARY

     Five chemicals have been identified as potentially qualifying for revision on the basis of
new IRIS or OPP health assessments that could impact the MCLG. These are beryllium, 1,1-
dichloroethylene, lindane, oxamyl, and picloram.  This tentative identification of chemicals
potentially qualifying for revision was conducted independently of other considerations (e.g.,
analytical and treatment technology, occurrence data), which may influence the final selection of
contaminants to be revised.

     Three chemicals - cyanide, di(2-ethylhexyl)adipate and thallium - are high priority for
reevaluation because of reproductive and/or developmental concerns. New IRIS  risk
assessments of these chemicals have been initiated.  The new risk assessments are expected to be
completed in the 2004/2005 time frame for cyanide, 2003/2004 for di(2-ethylhexyl)adipate, and
2004/2005 for thallium (USEPA, 2003b).

     New data have become available regarding the effect of fluoride on bone, and the
contribution of various sources to total fluoride exposure (WHO, 2002). At the request of EPA,
NAS has initiated a review of the toxicological data on fluoride, including effect on bone, as well
as the relative contribution of various sources to the overall exposure to fluoride.

     Hexavalent chromium is under study by the National Toxicology Program (NTP, 2002).
Once the subchronic and chronic studies are completed, the Agency will evaluate the
toxicological data with regard to their impact on the present MCLG.

     Table 5 summarizes the review process applied to each of the 68 chemicals under
consideration.

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Table 1. Cancer classification systems used by EPA (USEPA, 1986; USEPA, 1989; USEPA,
1992)
      Three-category approach for
          establishing MCLGs
    Corresponding five-group classification
       system of 1986 cancer guidelines
                             MCLG generally set at zero
 Category I:

 Known or probable human
 carcinogens: Strong evidence of
 carcinogenicity

 Sufficient human or animal evidence of
 carcinogenicity.
Generally Group A or B:

A: Human carcinogen
Sufficient evidence from epidemiological studies
to support a causal association.
B: Probable human carcinogen
Bl: Limited evidence of carcinogenicity from
epidemiological studies.
B2: Inadequate evidence or no data from
epidemiological studies; sufficient evidence from
animal studies.
    MCLG based on the RfD with an additional safety factor of up to 10 to account for
       possible carcinogenicity, or is based on excess cancer risk range of 105 to 106
 Category II:

 Limited evidence of carcinogenicity

 Some limited but insufficient evidence of
 carcinogenicity from animal data.
Generally Group C:

Possible human carcinogen

Limited evidence of carcinogenicity in animals in
the absence of human data.
                      MCLG established using the RfD approach
 Category III:

 Inadequate or no evidence of
 carcinogenicity in animals
Group D or Group E:

D: Not classifiable as to human
carcinogenicity
Inadequate human and animal evidence of
carcinogenicity, or no data available.
E: Evidence of non-carcinogenicity for
humans
No evidence of carcinogenicity in two different
animal species, or in both epidemiological and
animal studies.
                                         10

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             Table 2. Chemicals considered under the first Six-Year Review cycle
 (New RfD and/or cancer assessment have become available for nine chemicals given in bold).
Chemical
1. Acrylamide
2. Alachlor
3. Antimony
4. Asbestos (fibers > 10
|im in length)
5. Atrazine
6. Barium
7. Benzene
8. Benzo[a]pyrene
Regulation (month/year)
MCLG
mg/L
0
(1/91)
0
(1/91)
0.006
(7/92)
7 MFL
(1/91)
0.003
(1/91)
2
(7/91)
0
(7/87)
0
(7/92)
MCL
mg/L
TT
0.002
0.006
7 MFL
0.003
(1/91)
2
0.005
0.0002
RfD
mg/kg/d
0.0002
0.01
0.0004
—
0.005
0.07
—
—
Cancer
group
B2
B2
D
C2
C
D
A
B2
IRIS (year)
RfD
mg/kg/d
0.0002
(91)
0.01
(93)
0.0004
(91)
NA
0.035
(93)
0.07
(98)
0.004
NA
Cancer
group
B2
(91)
NA
NA
3
(88)
NA
D4
(98)
A5
(00)
B2
(92)
OPP (month/year)
RfD
mg/kg/d

0.01
(9/98)






Cancer
group

i
(9/98)






        1 Under the 1996 proposed cancer guidelines, alachlor is characterized as likely to be carcinogenic to
humans at high doses, but not likely at low doses.

         Asbestos: Group C based on limited evidence of carcinogenicity by the oral route; Group A by inhalation
exposure (USEPA, 1989).

        3 Asbestos: Limited animal evidence for carcinogenicity via ingestion, and epidemiologic data in this regard
are inadequate. Group A by inhalation exposure.

        4 Under the 1996 proposed cancer guidelines, barium is characterized as not likely to be carcinogenic to
humans following oral exposure.

        5 Under the 1996 proposed cancer guidelines, benzene is characterized as a known human carcinogen for all
routes of exposure.
                                                 11

-------
Table 2 (continued)
Chemical
9. Beryllium
10. Cadmium
11. Carbofuran
12. Carbon tetrachloride
13. Chlordane
14. Chromium
(total)
Cr(VI)
Cr (III)
Regulation (month/year)
MCLG
mg/L
0.004
(7/92)
0.005
(1/91)
0.04
(1/91)
0
(7/87)
0
(1/91)
0.1
(1/91)
MCL
mg/L
0.004
0.005
0.04
0.005
0.002
0.1
RfD
mg/kg/d
0.005
0.0005
0.005
0.0007
0.00006
0.005
Cancer
group
B26
D
E
B2
B2
D
IRIS (year)
RfD
mg/kg/d
0.002
(98)
0.0005
(91)
0.005
(87)
0.0007
(91)
0.0005
(98)
0.003
(98)
1.5
(98)
Cancer
group
Bl7
(98)
8
(91)
NA
B2
(91)
B29
(98)
D10
(98)
D11
(98)
OPP (month/year)
RfD
mg/kg/d




Canceled

Cancer
group






          EPA classified beryllium in Group B2, probable human carcinogen, based on clear evidence of its
carcinogenicity via inhalation or injection in several animal species. However, EPA also placed beryllium in
drinking water Category II for regulation (limited evidence of carcinogenicity considering the weight of evidence for
carcinogenicity via ingestion, potency, exposure, and pharmacokinetics). The MCLG was derived using the RfD and
applying an additional safety factor of 10 for possible carcinogenic potential.

        7 Bl based on inhalation exposure. Under the 1996 proposed cancer guidelines, inhaled beryllium is
characterized as a likely carcinogen in humans, and the human carcinogenic potential of ingested beryllium cannot
be determined.

        8 Carcinogenicity studies of cadmium administered orally to animals have shown no evidence of
carcinogenic response. B1  based on inhalation exposure.

        9 Under the 1996  proposed cancer guidelines, chlordane is characterized as a likely human carcinogen by
all routes of exposure.
        10
          Under the 1996 proposed cancer guidelines, the oral carcinogenicity of Cr VI cannot be determined.

          Under the 1996 proposed cancer guidelines, there are inadequate data to determine the potential
carcinogenicity of Cr III.
                                                    12

-------
Table 2 (continued)
Chemical
15. Copper
16. Cyanide
17. 2,4-D (2,4-Dichloro
phenoxyacetic acid)
18. Dalapon (2,2-di
chloropropionic acid)
19. Di(2-ethylhexyl)
adipate
20. Di(2-ethylhexyl)
phthalate
21. l,2-Dibromo-3-
chloropropane (DBCP)
22. Dichlorobenzene o-
( 1 ,2-Dichlorobenzene)
23. Dichlorobenzene p-
( 1 ,4-Dichlorobenzene)
24. Dichloroethane(l,2-)
(Ethylene dichloride)
25. Dichloroethylene
(1,1-)
26. Dichloroethylene
(cis-1,2-)
27. Dichloroethylene
(trans-1,2-)
28. Dichloromethane
(methylene chloride)
29. Dichloropropane
(1,2-)
Regulation (month/year)
MCLG
mg/L
1.3 12
(6/91)
0.2
(7/92)
0.07
(1/91)
0.2
(7/92)
0.4
(7/92)
0
(7/92)
0
(1/91)
0.6
(1/91)
0.075
(7/87)
0
(7/87)
0.007
(7/87)
0.07
(1/91)
0.1
(1/91)
0
(7/92)
0
(1/91)
MCL
mg/L
TT12
0.2
0.07
0.2
0.4
0.006
0.0002
0.6
0.075
0.005
0.007
0.07
0.1
0.005
0.005
RfD
mg/kg/d
—
0.02
0.01
0.03
0.6
0.02
—
0.09
0.1
—
0.009
0.01
0.02
0.06
—
Cancer
group
D
D
D
D
C
B2
B2
D
C
B2
C
D
D
B2
B2
IRIS (year)
RfD
mg/kg/d
NA
0.02
(87)
0.01
(87)
0.03
(88)
0.6
(92)
0.02
(88)
NA
(91)
0.09
(90)
NA
(94)
NA
0.046
(02)
NA
0.02
(88)
0.06
(91)
NA
(91)
Cancer
group
D
(88)
D
NA
NA
C
(92)
B2
(88)
NA
D
(90)
NA
B2
(91)
C13
(02)
D
(90)
NA
B2
(91)
NA
OPP (month/year)
RfD
mg/kg/d



Canceled


Canceled
Canceled

Canceled



Canceled

Cancer
group


D
(7/96)












        12
        13
NAS (2000a) considered that the MCLG for copper was appropriate. Copper action level: 1.3 mg/L.




Under the draft revised guidelines for carcinogen risk assessment (USEPA, 1999), the data for 1,1-DCE
are inadequate for an assessment of human carcinogenic potential by the oral route.




                                                 13

-------
Table 2 (continued)
Chemical
30. Dinoseb
31. Diquat
32. Endothall
33. Endrin
34. Epichlorohydrin
35. Ethylbenzene
36. Ethylene dibromide
(EDB; 1,2-Dibromoeth-
ane)
37. Fluoride14
38. Glyphosate
39. Heptachlor
40. Heptachlor epoxide
Regulation (month/year)
MCLG
mg/L
0.007
(7/92)
0.02
(7/92)
0.1
(7/92)
0.002
(7/92)
0
(1/91)
0.7
(1/91)
0
(1/91)
4.0
(11/85)
0.7
(7/92)
0
(1/91)
0
(1/91)
MCL
mg/L
0.007
0.02
0.1
0.002
TT
0.7
0.00005
4.0
(4/86)
0.7
0.0004
0.0002
RfD
mg/kg/d
0.001
0.0022
0.02
0.0003
NA
0.1
—
0.11 15
0.1
0.0005
0.000013
Cancer
group
D
D
D
D
B2
D
B2
—
D
B2
B2
IRIS (year)
RfD
mg/kg/d
0.001
(89)
0.0022
(87)
0.02
(87)
0.0003
(89)
NA
0.1
(91)
NA
0.0616
0.1217
(87)
0.1
(89)
0.0005
(91)
0.000013
(91)
Cancer
group
D
(89)
NA
NA
D
(89)
B2
(92)
D
(91)
B2
(91)
NA
D
(89)
B2
(91)
B2
(91)
OPP (month/year)
RfD
mg/kg/d
Canceled
0.005
(3/95)

Canceled


Canceled

2
(9/93)
0.0005
(92)
0.000013
(92)
Cancer
group

E
(3/95)






E
(9/93)
B2
(92)
B2
(92)
        14
          NAS (1997) established a tolerable upper intake level (UL) for fluoride of 10 mg/day for children older
than 8 years and for adults, based on protection against skeletal fluorosis. The 1997 NAS evaluation of fluoride does
not affect the MCLG.
        15 ,
         1 This is the RfD calculated from the MCLG assuming 70kg body weight and intake of 2L/day.  The
MCLG was developed from a lowest effect level for crippling skeletal fluorosis of 20 mg/day with continuous
exposures over a 20-year or longer period. The LOAEL was divided by an uncertainty factor of 2.5 and a drinking
water intake of 2L/day to obtain the MCLG.
        16
        17
For objectionable dental fluorosis, a cosmetic effect.

For crippling skeletal fluorosis in humans.
                                                  14

-------
Table 2 (continued)
Chemical
41. Hexachlorobenzene
42. Hexachlorocyclo-
pentadiene
43. Lead
44. Lindane (y-hexa-
chlorocyclohexane)
45. Mercury (Inorganic)
46. Methoxychlor
47. Monochlorobenzene
(Chlorobenzene)
48. Nitrate (as N)
Regulation (month/year)
MCLG
mg/L
0
(7/92)
0.05
(7/92)
0
(6/91)
0.0002
(1/91)
0.002
(1/91)
0.04
(1/91)
0.1
(1/91)
10
(1/91)
MCL
mg/L
0.001
0.05
r-pr-p 20
0.0002
0.002
0.04
0.1
10
RfD
mg/kg/d
0.0008
0.007
—
0.0003
0.0003
0.005
0.02
1.6 24
Cancer
group
B2
D
B2
C
D
D
D
D
IRIS (year)
RfD
mg/kg/d
0.0008
(91)
0.006 18
(01)
NA
0.0003
(88)
0.0003 23
(97)
0.005
(90)
0.02
(90)
1.624
(91)
Cancer
group
B2
(91)
	 19
(01)
B2
(88)
NA
23
(97)
D
(90)
D
(90)
NA
OPP (month/year)
RfD
mg/kg/d
Canceled


0.0047 21
(7/02)




Cancer
group



	 22
(7/02)




        18
          RfD of HCCP based on the same lexicological study as that of the MCLG but using benchmark dose
modeling for the dose-response analysis.
        19
          HCCP: E by inhalation exposure; the potential for carcinogenicity by the oral route is unknown.

          Lead action level: 0.015 mg/L.
        21
          Lindane: An additional safety factor of three was applied to the RfD to take into account the evidence for
increased susceptibility of the young demonstrated in developmental neurotoxicity and reproductive toxicity studies
in rats, giving a population adjusted dose (PAD) of 0.0016 mg/kg/day.
        22
          Under the draft revised guidelines for carcinogen risk assessment (USEPA, 1999), the data for lindane
show suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.
        23 -
         1 Mercury Study Report to Congress assessment (USEPA, 1997): RfD for inorganic Hg of 0.0003
mg/kg/day retained. Under the 1996 proposed cancer guidelines, inorganic mercury is not likely to be a human
carcinogen at levels found in water.
        24
          RfDs for nitrate and nitrite, in mg N/kg/day, back-calculated from epidemiological studies on the basis of
0.64 L/day  and a 4-kg infant.
                                                   15

-------
Table 2 (continued)
Chemical
49. Nitrite (as N)
Nitrate + Nitrite (as N)
50. Oxamyl (Vydate)
51. Pentachlorophenol
52. Picloram
53. Polychlorinated
biphenyls (Aroclors)
54. Selenium26
55. Simazine
56. Styrene
57. 2,3,7,8-TCDD
(Dioxin)
58. Tetrachloroethylene
("perc")
59. Thallium
60. Toluene
61. Toxaphene
Regulation (month/year)
MCLG
mg/L
1
(1/91)
10
(1/91)
0.2
(7/92)
0
(1/91)
0.5
(7/92)
0
(1/91)
0.05
(1/91)
0.004
(7/92)
0.1
(1/91)
0
(7/92)
0
(1/91)
0.0005
(7/92)
1
(1/91)
0
(1/91)
MCL
mg/L
1
10
0.2
0.001
0.5
0.0005
0.05
0.004
0.1
3xlO-8
0.005
0.002
1
0.003
RfD
mg/kg/d
0.1624
—
0.025
0.03
0.07
—
0.005
0.005
0.2
io-9
0.01
0.00007
0.2
NA
Cancer
group
D
—
E
B2
D
B2
D
C
C
B2
B2
D
D
B2
IRIS (year)
RfD
mg/kg/d
O.I25
(87)
—
0.025
(87)
0.03
(91)
0.07
(87)
2 - 7 xlO'5
(96)
0.005
(91)
0.005
(93)
0.2
(90)

0.01
(88)
0.00008
(90)
0.2
(90)
NA
Cancer
group
NA
—
NA
B2
(91)
NA
B2
(96)
D
(91)
NA
NA

NA
D
(90)
D
(90)
B2
(91)
OPP (month/year)
RfD
mg/kg/d


0.001
(10/00)

0.2
(4/98)





Canceled
Canceled

Canceled
Cancer
group


E
(10/00)

E
(4/98)









        25
          RfD for nitrite, in mg N/kg/day, back-calculated from epidemiological studies on the basis of 1 L/day
and a 10-kg child. It is equivalent to a RfD of 0.16 mg/kg/day if 0.64 L/day and a 4-kg infant were used.
        26
           NAS (2000b) tolerable upper intake level (UL) for selenium for adolescents and adults is 0.4 mg/day, a
value equivalent to the RfD of 0.005 mg/kg/day established in 1991.




                                                   16

-------
Table 2 (continued)
Chemical
62. 2,4,5-TP (Silvex;
2,4,5-Trichlorophenoxy
propionic acid)
63. Trichlorobenzene
(1,2,4-)
64. Trichloroethane
(1,1,1-)
65. Trichloroethane
(1,1,2-)
66. Trichloroethylene
67. Vinyl chloride
68. Xylenes (total)
Regulation (month/year)
MCLG
mg/L
0.05
(1/91)
0.07
(7/92)
0.20
(7/87)
0.003
(7/92)
0
(7/87)
0
(7/87)
10
(1/91)
MCL
mg/L
0.05
0.07
0.20
0.005
0.005
0.002
10
RfD
mg/kg/d
0.008
0.01
0.035
0.004
—
—
2
Cancer
group
D
D
D
C
B2
A
D
IRIS (year)
RfD
mg/kg/d
0.008
(88)
0.01
(92)
NA
(91)
0.004
(91)
NA
(89)
0.003
(00)
2
(88)
Cancer
group
D
(88)
D
(91)
D
(90)
C
(91)
NA
(89)
A27
(00)
D
(88)
OPP (month/year)
RfD
mg/kg/d
Canceled


Canceled
Canceled


Cancer
group







        27 ,
          Under the 1996 proposed cancer guidelines, vinyl chloride is a known human carcinogen by the
inhalation route of exposure, based on human epidemiological data, and by analogy the oral route because of
positive animal bioassay data as well as pharmacokinetic data allowing dose extrapolation across routes.
                                                  17

-------
Table 3. Assessment by IRIS, OPP, ATSDR, and NAS of chemicals considered under the first Six-Year Review cycle
Chemical, Year Regulated
Acrylamide '91
Alachlor '91
Antimony '92
Asbestos '91
Atrazine '91
Barium '91
Benzene '87
Benzo[a]pyrene '92
Beryllium '92
Cadmium '91
Carboruran '91
Carbon tetrachloride '87
Chlordane '91
Chromium '91
Copper '91
Cyanide '92
90/91
IRIS

IRIS






IRIS

IRIS




92/93

IRIS
ATSDR

IRIS
ATSDR

IRIS








94/95







ATSDR



ATSDR
ATSDR



96
















97






ATSDR








ATSDR
98

OPP



IRIS


IRIS



IRIS
IRIS


99









ATSDR






00






IRIS






ATSDR
NAS

01



ATSDR












02








ATSDR




NTP1


>03
IRIS
IRIS
IRIS
IRIS
OPP
ATSDR


IRIS

IRIS
OPP
IRIS


ATSDR
IRIS
IRIS
  1 Subchronic and chronic lexicological studies of Cr VI initiated by NTP.




                                                     18

-------
Table 3 (continued)
Chemical, Year Regulated
2,4-D '91
Dalapon '92
Di (2-ethylhexyl)adipate '92
Di (2-ethylhexyl)phthalate '92
1,2-DBCP '91
1,2-Dichlorobenzene '91
1,4-Dichlorobenzene '87
1,2-Dichloroethane '87
1,1-Dichloroethylene '87
cis-l,2-Dichloroethylene '91
trans- 1,2-Dichloroethylene '91
Dichloromethane '92
1,2-Dichloropropane '91
Dinoseb '92
Diquat '92
Endothall '92
Endrin '92
Epichlorohydrin '91
90/91




IRIS
IRIS

IRIS

IRIS

IRIS
IRIS





92/93


IRIS

ATSDR












IRIS
94/95






IRIS

ATSDR





OPP



96









ATSDR
ATSDR





ATSDR

97


















98






ATSDR











99


















00











ATSDR






01







ATSDR










02



ATSDR




IRIS









^03
OPP

IRIS
IRIS

IRIS
IRIS
IRIS






OPP
OPP


                                                        19

-------
Table 3 (continued)
Chemical, Year Regulated
Ethylbenzene '91
Ethylene dibromide '91
Fluoride '86
Glyphosate '92
Heptachlor '91
Heptachlor epoxide '91
Hexachlorobenzene '92
Hexachlorocyclopentadiene
'92
Lead '91
Lindane '91
Mercury '91 (Inorganic)
Methoxychlor '91
Monochlorobenzene '91
90/91
IRIS
IRIS


IRIS
IRIS
IRIS




IRIS
IRIS
ATSDR
92/93

ATSDR
NAS
OPP
OPP
ATSDR
OPP
ATSDR







94/95










IRIS


96













97


NAS







EPA2


98













99







ATSDR
ATSDR
ATSDR
ATSDR


00
ATSDR












01







IRIS





02






ATSDR


OPP

ATSDR

^03
IRIS
IRIS
ATSDR
NAS
IRIS







OPP

       ; Mercury Study Report to Congress (USEPA, 1997).
                                                              20

-------
Table 3 (continued)
Chemical, Year Regulated
Nitrate '91
Nitrite '91
Oxamyl '92
Pentachlorophenol '91
Picloram '92
PCBs '91
Selenium '91
Simazine '92
Styrene '91
2,3,7,8-TCDD '92
Tetrachloroethylene '91
Thallium '92
Toluene '91
Toxaphene '91
2,4,5-TP '91
90/91
IRIS


IRIS


IRIS

IRIS


IRIS
IRIS
IRIS

92/93







IRIS
ATSDR


ATSDR



94/95
NAS
NAS













96





IRIS







ATSDR

97










ATSDR




98




OPP




ATSDR





99















00


OPP


ATSDR
NAS





ATSDR


01



ATSDR











02















203



IRIS

IRIS
ATSDR
OPP
IRIS3
IRIS
IRIS
IRIS
IRIS


         Joint IRIS/ Styrene Information and Research Council.
                                                                 21

-------
Table 3 (continued)
Chemical, Year Regulated
1,2,4-Trichlorobenzene '92
1,1,1-Trichloroethane '87
1,1,2-Trichloroethane '92
Trichloroethylene '87
Vinyl chloride '87
Xylenes '91
90/91

IRIS
IRIS



92/93
IRIS





94/95

ATSDR



ATSDR
96






97



ATSDR
ATSDR

98






99






00




IRIS

01






02






203

IRIS

IRIS

IRIS
                                                        22

-------
Table 4.  Evaluation of the literature search for reproductive and developmental toxicity
              (New IRIS assessments initiated for chemicals given in bold)
Chemical
Cyanide
Dalapon
Di(2-ethylhexyl)adipate
cis- 1 ,2-Dichloroethy lene
trans-1,2-
Dichloroethylene
Dinoseb
Endrin
Fluoride '
Monochlorobenzene
Comments
Based on NTP (1993) 13-week study, ATSDR (1997) identified a NOAEL of 4.5
mg/kg/day for reproductive effects in male rats (decreases in epididymis and testis
weights and reduction in spermatid head size and count). The current 1992 NPDWR
RfD of 0.02 mg/kg/day is based on a NOAEL of 10.8 mg/kg/day in a 2-year study
for weight loss, thyroid effects and myelin degeneration in rats. New IRIS
assessment initiated.
Literature search performed for the Six- Year Review did not identify any
information to support consideration of a revision to the RfD (and therefore the
MCLG).
Current RfD/MCLG of 1992 based on a developmental toxicity study in rats that
identified a NOAEL of 170 mg/kg/day. WHO (1996) and the European
Commission (EC 1999) considered the LOAEL to be 170 mg/kg/day and the
NOAEL to be the next lower dose of 28 mg/kg/day. Similarly, IARC (2000)
indicated effects at 170 mg/kg/day. New IRIS assessment initiated to reevaluate the
available developmental and reproductive studies, and to evaluate new studies that
have become available on the toxicity of DEHA and its metabolites.
Literature search performed for the Six- Year Review did not identify any
information to support consideration of a revision to the RfD (and therefore the
MCLG).
Literature search performed for the Six-Year Review did not identify any
information to support consideration of a revision to the RfD (and therefore the
MCLG).
Current RfD based on three-generation reproductive study in rats. Developmental
effects seen at higher doses than are reproductive effects. New information does not
support need to revise RfD/MCLG.
Reproductive and developmental effects occur at doses above those causing
hepatotoxicity, the critical effect. New information does not support need to revise
RfD/MCLG.
No new studies identified in the literature search indicating that fluoride adversely
affects reproductive or developmental endpoints. Epidemiological studies show no
evidence of an association between the consumption of fluoridated drinking water
by mothers and increased risk of spontaneous abortion or congenital malformation
(WHO, 2002).
Literature search performed for the Six- Year Review did not identify any
information to support consideration of a revision to the RfD (and therefore the
MCLG).
     1 NAS assessment of fluoride initiated
                                         23

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Table 4 (continued)
 Chemical
Comments
 Nitrate
Current RfD/MCLG established to protect infants, the most susceptible segment of
the population. Epidemiological studies of maternal nitrate exposure from drinking
water and developmental effects in offspring or spontaneous abortion are
inconclusive (Croen et al, 1997). Reproductive and developmental effects in
experimental animals are not the critical effects. Epidemiological studies of nitrate
in drinking water and cancer incidence, including non-Hodgkin's lymphoma, a
childhood cancer, and bladder cancer are inconclusive (Weyer et al., 2001; Ward et
al., 1996). New information does not support need to revise RfD/MCLG.
 Nitrite
Current RfD/MCLG is protective of methemoglobinemia in infants, the most
susceptible segment of the population. Sodium nitrite was tested in mice by NIEHS
(Chapin et al., 1997) using the Reproductive Assessment by Continuous Breeding
protocol; reproductive effects are not the critical effects and did not occur at doses
as high as 425 mg nitrite/kg/day. New information does not support need to revise
RfD/MCLG.
 Selenium
NAS (2000b) assessment of Se confirms the current RfD of 1991 based on
epidemiological studies of selenosis in humans. Epidemiological studies of Se
deficiency and male infertility, pregnancy-induced hypertension and congenital
heart disease, are inconclusive (ATSDR, 1996). In experimental animals,
reproductive and developmental toxicity are not the critical effects (NTP, 1996).
New information does not support need to revise RfD/MCLG.
 Thallium
ATSDR (1992) identified LOAELs in rats for developmental effects (impairment of
learning ability) and reproductive effects (histological alteration of testis) of 0.08
and 0.7 mg/kg/day, respectively, compared to the NOAEL of 0.2 mg/kg/day, the
highest dose tested and the basis of the NPDWR. Also, the present NOAEL of 0.2
mg/kg/day is debatable: Cal/EPA (1999) considers the NOAEL to be the next lower
dose tested of 0.04 mg/kg/day for changes in blood chemistry, alopecia and
lacrimation in rats. Evaluation of developmental neurological effects of TI by the
oral route need to be assessed. New IRIS assessment initiated.
 2,4,5-TP (Silvex)
Current RfD protective of chronic liver effects would also protect against
fetotoxicity and teratogenicity. New information does not support need to revise
RfD/MCLG.
 1,2,4-Trichlorobenzene
Current RfD based on a multigeneration reproductive study in rats. New
information does not support need to revise RfD/MCLG.
 1,1,2-Trichloroethane
Literature search performed for the Six-Year Review did not identify any
information to support consideration of a revision to the RfD (and therefore the
MCLG).
                                                   24

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Table 5. Overall review of chemicals
Chemical
Acrylamide
Alachlor
Antimony
Asbestos
Atrazine
Barium
Benzene
Benzo[a]pyrene
Beryllium
Cadmium
Carbofuran
Carbon tetrachloride
Chlordane
Chromium
Copper
RfD/Cancer
group
changed

Yes






Yes




Yes

Ongoing
IRIS or OPP
assessment
Yes
Yes
Yes
Yes
Yes


Yes

Yes
Yes
Yes

NTP1
Yes
MCLG = 0






Yes





Yes


Recent (>97)
EPA
assessment
available





Yes
Yes

Yes



Yes
Yes

Evaluate
Literature
search for
repro/develop
endpoints
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
High priority,
nominate for
new IRIS
assessment















Evaluate
Literature
search for other
tax endpoints
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
Nominatefor
new
assessment















        Ongoing NTP subchronic and chronic lexicological studies for Cr VI (NTP, 2002).




                                                                25

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Table 5 (continued)
Chemical
Cyanide
2,4-D
Dalapon
Di(2-ethylhexyl) adipate
Di(2-ethylhexyl)
phthalate
1,2-DBCP
1 ,2-Dichlorobenzene
1 ,4-Dichlorobenzene
1 ,2-Dichloroethane
1 , 1 -Dichloroethy lene
Dichloroethylene
(cis-1,2-)
Dichloroethylene (trans-
1,2-)
Dichloromethane
1 ,2-Dichloropropane
RfD/Cancer
group
changed









Yes




Ongoing
IRISorOPP
assessment

Yes


Yes

Yes
Yes
Yes





MCLG = 0





Yes






Yes
Yes
Recent (z97)
EPA
assessment
available









Yes




Evaluate
Literature
search for
repro/develop
endpoints
Yes
No
Yes
Yes
No
No
No
No
No
No
Yes
Yes
No
No
High priority,
nominatefor
new IRIS
assessment
Yes

No
Yes






No
No


Evaluate
Literature
search for other
tax endpoints
No
No
Yes
No
No
No
No
No
No
No
Yes
Yes
No
No
Nominatefor
new
assessment


No







No
No


                                                        26

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Table 5 (continued)
Chemical
Dinoseb
Diquat
Endothall
Endrin
Epichlorohydrin
Ethylbenzene
Ethylene dibromide
Fluoride
Glyphosate
Heptachlor
Heptachlor epoxide
Hexachlorobenzene
Hexachlorocyclopenta-
diene
Lead
Lindane
RfD/Cancer
group
changed

Yes






Yes





Yes
Ongoing
IRISorOPP
assessment

Yes
Yes


Yes
Yes

Yes






MCLG = 0




Yes




Yes
Yes
Yes

Yes

Recent (z97)
EPA
assessment
available












Yes

Yes
Evaluate
Literature
search for
repro/develop
endpoints
Yes
No
No
Yes
No
No
No
Yes
No
No
No
No
No
No
No
High priority,
nominatefor
new IRIS
assessment
No


No



No







Evaluate
Literature
search for other
tax endpoints
Yes
No
No
Yes
No
No
No
Yes
No
No
No
No
No
No
No
Nominatefor
new
assessment
No


No



Yes (NAS)







                                                        27

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Table 5 (continued)
Chemical
Mercury (inorganic)
Methoxychlor
Monochlorobenzene
Nitrate
Nitrite
Oxamyl
Pentachlorophenol
Picloram
PCBs
Selenium
Simazine
Styrene
2,3,7,8-TCDD
Tetrachloroethylene
Thallium
Toluene
RfD/Cancer
group
changed





Yes

Yes








Ongoing
IRISorOPP
assessment

Yes




Yes

Yes

Yes
Yes
Yes
Yes

Yes
MCLG = 0
















Recent (z97)
EPA
assessment
available
Yes




Yes

Yes








Evaluate
Literature
search for
repro/develop
endpoints
No
No
Yes
Yes
Yes
No
No
No
No
Yes
No
No
No
No
Yes
No
High priority,
nominatefor
new IRIS
assessment


No
No
No




No




Yes

Evaluate
Literature
search for other
tax endpoints
No
No
Yes
Yes
Yes
No
No
No
No
No (NAS, 2000)
No
No
No
No
No
No
Nominatefor
new
assessment


No
No
No











                                                        28

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Table 5 (continued)
Chemical
Toxaphene
2,4,5-TP (Silvex)
Trichlorobenzene (1,2,4-)
Trichloroethane (1,1,1-)
Trichloroethane (1,1,2-)
Trichloroethylene
Vinyl chloride
Xylenes
RfD/Cancer
group
changed








Ongoing
IRISorOPP
assessment



Yes

Yes

Yes
MCLG = 0
Yes





Yes

Recent (z97)
EPA
assessment
available






Yes

Evaluate
Literature
search for
repro/develop
endpoints
No
Yes
Yes
No
Yes
No
No
No
High priority,
nominatefor
new IRIS
assessment

No
No

No



Evaluate
Literature
search for other
tax endpoints
No
Yes
Yes
No
Yes
No
No
No
Nominatefor
new
assessment

No
No

No



                                                        29

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REFERENCES

ATSDR (Agency for Toxic Substances and Disease Registry). 1992. lexicological Profile for Thallium. Available
at: www.atsdr.cdc.gov/toxpro2.html#-A-

ATSDR. 1996.  Toxicological Profile for Selenium. Available at: www.atsdr.cdc.gov/toxpro2.html#-A-

ATSDR. 1997.  Toxicological Profile for Cyanide. Available at: www.atsdr.cdc.gov/toxpro2.htmM-A-

ATSDR. 1999.  Toxicological Profile for Lead. Available at: www.atsdr.cdc.gov/toxpro2.html#-A-

Avery AA.  1999. Infantile methemoglobinemia: Reexamining the role of drinking water nitrates. Environ Health
Perspect 107(7):583-586.

Barrett JH, Parslow RC, McKinney PA, et al. 1998. Nitrate in drinking water and the incidence of gastric,
esophageal, and brain cancer in Yorkshire, England. Cancer Causes Control 9:153-159.

Cal/EPA (California Environmental Protection Agency). 1997. Public health goals for nitrate and nitrite in drinking
water. December 1997. Available at: http://www.oehha.ca.gov/water/phg/allphgs.html

Cal/EPA. 1999.  Public health goals for thallium in drinking water. February 1999. Available at:
http://www.oehha.ca.gov/water/phg/allphgs.html.

Chapin R, Gulati D, Barnes LH.  1997.  Sodium nitrite. Environ Health Perspect 105 (Suppl 1). February 1997. pp.
345.

Croen LA, Todoroff K, Shaw GM.  1997.  Maternal dietary nitrate exposure and risk for neural tube defects. Am J
Epidemiol 145:830.

EC (European Commission). 1999.  European Commission Scientific Committee on Toxicity, Ecotoxicity and the
Environment: Opinion on the lexicological characteristics and risks of certain citrates and adipates used as a
substitute for phthalates as plasticisers in certain soft PVC products. 28 September 1999. Brussels, Belgium.
Available at: nttp://europa.eu.int/comm/food/fs/sc/sct/out45_en.pdf.

IARC (International Agency for Research on Cancer).  1999. IARC Monographs on the Evaluation of Carcinogenic
Risks to Humans. Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide. Vol. 71: 1,2-
Dibromo-3-chloropropane, pp. 479-500; Dichloromethane, pp. 251-315; 1,2-Dichloropropane, pp. 1393-1400;
Epichlorohydrin, pp. 603-628. Lyon, France.

IARC.  2000. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Some Industrial Chemicals.
Lyon, France. Vol. 77: Di(2-ethylhexyl)adipate, pp. 149-175. Lyon, France.

IARC.  2001. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Some Thyrotropic Agents.
Vol. 79: Chlordane and heptachlor, pp. 411-492; Hexachlorobenzene, pp. 493-568; Toxaphene, pp. 569-604. Lyon,
France.

Knobeloch L, Salna B, Hogan A, et al. 2000. Blue babies and nitrate-contaminated well water. Environ Health
Perspect 108(7):675-678.

NAS (National Academy of Sciences).  1995. Nitrate and nitrite in drinking water. Washington, D.C. National
Academy Press. Available at: http://www.nap.edv^ooks/NI000114/html/index.html.

NAS. 1997. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington,
D.C. National Academy Press. Available at: http://www.nap.edu/books/0309063507/html/index.html.

NAS. 2000a. Copper in drinking water. Washington, D.C. National Academy Press. Available at:
http://books.nap.edv^ooks/0309069394/html/index.html.

NAS. 2000b. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, D.C.


                                                   30

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National Academy Press. Available at: http:^ooks.nap.edu/books/0309069351/html/index.html.

NDWAC (National Drinking Water Advisory Council). 2000. Recommended guidance for review of existing
national primary drinking water regulations, November 2000. Available at:
http ://www. epa. gov/safewater/ndwac/guidfnl.pdf.

NTP (National Toxicology Program).  1993. Toxicity studies of sodium cyanide, (CAS No. 143-33-9) administered
by dosed water to F344/N rats and B6C3F1 mice. Available at:
http://ntp-server.niehs.nih.gov/cgi/iH_Indexes/ALL_SRCH/iH_ ALL_SRCH_Frames.html.

NTP.  1996.  Sodium selenate (rats), CAS No.  13410-01-0). Study number: RDGT 94011.  May 1, 1996. Available
at: http://ntp-server.niehs.nih.gov/cgi/iH_Indexes/ALL_SRCH/iH_ALL_SRCH_Frames.html.

NTP.  2001.  TR-495. Toxicology and carcinogenesis studies of sodium nitrite (CAS No. 7632-00-00) in F344/N rats
andB6C3F! mice. Available at: http://ntp-server.niehs.nih.gov/htdocs/LT-studies/tr495.html.

NTP.  2002.  NTP study of the hexavalent chromium compound sodium dichromate dihydrate. Available at:
http://ntp-server.niehs.nih.gov/htdocs/Studies/HexChromium/hexchromiumpg.html

USEPA.  1986. Guidelines for carcinogen risk assessment. FR Vol. 51, No. 185: 33992-34003. September 24, 1986.
Available at: http://cfpub.epa.gov/ncea/cfm/cancer.cfm?ActType=default.

USEPA.  1989. National primary and secondary drinking water regulations; Proposed Rule. FR Vol. 54, No. 97:
22062-22094. May 22, 1989.

USEPA.  1992. National primary drinking water regulations; Synthetic organic chemicals and inorganic chemicals;
Final Rule. FR Vol. 57, No. 138:  31776-31849. July 17, 1992.

USEPA.  1996. Proposed guidelines for carcinogen risk assessment. FR Vol. 61, No. 79:  17960-18011. April 23,
1996. Available at: http://cfpub.epa.gov/ncea/cfm/cancer.cfm?ActType=default.

USEPA.  1997. Mercury Study Report to Congress. December 1997. Office of Air Quality Planning & Standards
and Office of Research and Development. EPA-452/R-97-009. Available at:
http ://www. epa. gov/ttncaaal/t3/reports/volumes .pdf.

USEPA.  1999. Guidelines for carcinogen risk assessment. Review Draft, Office of Research and Development.
NCEA-F-0644. July 1999.  US EPA Risk Assessment Forum. Washington D.C. Available at:
http://www.epa.gov/ncea/raf/cancer.htm.

USEPA. 2000. EPA Summary Report. Characterization of data variability and uncertainty: Health effects
assessments in the Integrated Risk Information System (IRIS). In response to Congress, HR 106-379. National
Center for Environmental Assessment, Office of Research and Development, Washington, D.C. EPA/635/R-
00/005F. Available at: http://www.epa.gov/ncea/pdfs/iris/ncea_repf.pdf.

USEPA. 2002. Integrated Risk Information System (IRIS); Announcement of 2002 Program;  Request for
information. FR Vol. 67, No.6:1212-1215.  January 9, 2002. Available at:
http://www.epa.gov/fedrgstr/EPA-GENERAL/2002/January/Day-09/g511 .htm

USEPA. 2003a. EPA Protocol for review  of existing national primary drinking water regulations. EPA 815-R-03-
002. Final. June 2003.

USEPA. 2003b. Integrated Risk Information System (IRIS); Announcement of 2003 Program; Request for
information and Announcement of Workshop.  FR Vol. 68, No.24:5870-5873. February 5, 2003. Available at:
http://www.epa.gov/fedrgstr/EPA-TOX/2003/February/Day-05/t2768.htm

Van Loon AJ, Botterweck AA, Goldbohm RA, et al.  1998.  Intake of nitrate and nitrite and the risk of gastric
cancer: A prospective cohort study. Br J Cancer 78:129-135.

Ward MH, Mark SD, Cantor KP, et al.  1996. Drinking water nitrate and the risk of non-Hodgkin's lymphoma.

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Epidemiology 7:465-471.

Weyer PJ, Cerhan JR, Cross BC, et al.  2001.  Municipal drinking water nitrate level and cancer risk in older
women: the Iowa Women's Health Study. Epidemiology 12(3):327-338.

WHO (World Health Organization).  1996.  Guidelines for drinking-water quality, 2nd ed.  Vol2: Health criteria
and other supporting information. Geneva, Switzerland. Available at:
http://www.who.int/water_sanitation_health/GDWQ/Chemicals/Chemlist.html.

WHO. 1998. Guidelines for drinking-water quality, 2nd ed. Addendum to Vol. 1:  Recommendations. Geneva,
Switzerland. Available at: http://www.who.int/water_sanitation_health/GDWQ/Chemicals/Chemlist.html.

WHO. 2002. World Health Organization. Environmental Health Criteria No. 227: Fluorides.  Geneva, Switzerland.
Available at: http://www.inchem.org/.
                                                  32

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                      EPA  822-R-03-008

Six-Year Review -  Chemical  Contaminants
Health Effects Technical Support Document

-------