March 31,  1987
                       2,3f 7,8-TETRACHLORODIBENZO-p-DIOXIN

                                 Health Advisory
                             Office  of Drinking Water
                       U.S.  Environmental Protection Agency
        The Health Advisory  (HA)  Program,  sponsored by  the Office of Drinking
   Water (ODW),  provides  information on the  health effects,  analytical  method-
   ology and treatment technology that  would be useful  in dealing with  the
   contamination of drinking water.   Health  Advisories  describe  nonregulatory
   concentrations  of drinking water  contaminants at which adverse health effects
   would not be  anticipated  to  occur over  specific exposure  durations.  Health
   Advisories contain  a margin  of safety to  protect sensitive members of the

        Health Advisories serve as informal  technical guidance to assist Federal,
   State and local officials responsible for protecting public health when
   emergency spills or contamination situations occur.  They are not to be
   construed as  legally enforceable  Federal  standards.  The  HAs  are subject to
   change as new information becomes available.

        Health Advisories are developed for  One-day, Ten-day, Longer-term
   (approximately  7 years, or 10% of an individual's lifetime) and Lifetime
   exposures based on  data describing noncarcinogenic end points of toxicity.
   Health Advisories do not  quantitatively incorporate  any potential carcinogenic
   risk from such  exposure.   For  those  substances that  are known or probable
   human carcinogens,  according to the  Agency classification scheme (Group A or
   B),  Lifetime  HAs are not  recommended. "ThireTJeTnlcal  concentration values for
   Group A or B  carcinogens  are correlated with carcinogenic risk estimates by
   employing a cancer  potency (unit  risk)  value together with assumptions for
   lifetime exposure and the consumption of  drinking water.  The cancer unit
   risk is usually derived from the  linear multistage model with 95% upper
   confidence limits.   This  provides  a  low-dose estimate of cancer risk to
   humans that is  considered unlikely to pose a carcinogenic risk in excess
   of the stated values.  Excess  cancer  risk estimates  may also  be calculated
   using the One-hit,  Weibull,  Logit or  Probit models.  There is no current
   understanding of the biological mechanisms involved  in cancer to suggest that
   any  one of these models is able to predict risk more accurately than another.
   Because each  model  is based  on differing  assumptions, the estimates that are
   derived can differ  by several  orders  of magnitude.

                     March 31, 1987
         This Health Advisory (HA)  is based on information presented in the Office
    of Drinking Water's Health Effects Criteria Document (CD) for 2,3,7,8-tetra-
    chlorodibenzo-p-dioxin (U.S.  EPA, 1985a).   The HA and CD formats are similar
    for easy reference.  'Individuals desiring further information on the toxico-
    logical data base or rationale  for risk characterization should consult the
    CD.  The CD is available for  review at each EPA Regional Office of Drinking
    Water counterpart (e.g., Water  Supply Branch or Drinking Water Branch), or
    for a fee from the National Technical Information Service, U.S. Department of
    Commerce, 5285 Port Royal Rd.,  Springfield, VA 22161, PB #86-117983/AS.  The
    toll-free number is (800) 336-4700; in the Washington, D.C. area:  (703) 487-4650c
    CAS No.  1746-01-6
    Structural Formula
         0  Dioxin;  TCDBD;  TCDD;  2,3,7,8-tetrachlorodibenzodioxin,  2,3,7,8-tetra-
            chlorodibenzo-1,4-dioxin;  2,3,7,8-TCDD.
         0  There are no commercial uses for TCDD.  (U.S. EPA,  1985a).

    Properties (U.S. "EPA, 1985a)
            Molecular Formula
            Molecular Weight
            Physical State
            Boiling Point
            Melting Point
            Vapor Pressure
            Water Solubility
            Log Octanol/Water Partition
            Odor Threshold
            Taste Threshold
            Conversion Factor
colorless solid, needle shape

303 - 305°C
3.5 x 10-9 inn, Hg* at 30.1°C
7.9 x 10-3 ug/L**
1.4 x 106

not available
not available
            * Cheng et al. (1983-1984).  Converted from 4.68 x 10~7 pascals.
            **Adams and Blaine (1985).
         0  TCDD is a synthetic chemical which has no natural sources.  TCDD is
            not produced directly but is formed as a by-product in the manufac-
            ture of a number of chlorinated phenolic compounds.  It can also be
            present in fly ash and flue gases of incinerators.

   2,3,7,8-Tetrachlorodibenzo-p-Dioxin                          March 31,  1987

          0  TCDD is extremely resistant to degradation once adsorbed onto soil
             with a reported half-life of 10-12 years.   TCDD has  a very low water
             solubility and binds readily to soil.   TCDD has been shown to migrate
             very slowly in soil.  TCDD also has been demonstrated to bioaccumulate
             in fish and mammals.

          8  TCDD has not been included in drinking  water surveys.   Given its
             limited solubility,  it is not expected  to  occur at detectable levels
             in either ground or  surface water.   TCDD has been reported to occur
             at low levels in some surface waters where it is probably bound to
             suspended materials.  TCDD has been found  in a number of freshwater
             fish at levels ranging from 1-695  ng/kg-  TCDD also  has been reported
             to occur at low levels in rice treated  with phenolic herbicides and
             in the fat of animals that grazed  on pasture treated with phenolic
             herbicides.  Due to  TCDD's physical characteristics, diet is expected
             to be a greater route of  exposure  than  drinking water;  however,  the
             available data are insufficient to evaluate the actual levels of
             either route (U.S. EPA,  1984a).

             Gavage  treatment with single  or  repeated  doses  of  2,3,7,8-TCDD  in  oil
             has  resulted  in absorption of approximately 50% of the dose
             (unspecified)  administered to guinea  pigs (Nolan et al.,  1979)  and
             approximately 70-83% of  the dose administered to rats  (1  or  50  ugAg)
             (Rose et al.,  1976;  Piper  et  al.,  1973) or  to hamsters (650  ug/kg)
             (Olson  et al.,  1980a).  Absorption of a single  oral dose  of  1.14 ng
             3H-2,3,7,8-TCDD/kg in corn oil by  a male  volunteer has been  estimated
             to be 88.5% (Poiger  and  Schlatter,  1986).

             Dietary administration of  0.5 or 1.4  ug 2,3,7,8-TCDD/kg/day  for 42
             days resulted in somewhat  reduced  gastrointestinal absorption by rats
             (approximately  50-60% of the  administered dose  was  absorbed)  (Fries
             and  Marrow,  1975).

             Percutaneous  absorption  of 2,3,7,8-TCDD (26 ng)  has been  estimated in
             rats to be approximately 40%  of  the absorption  of  an equivalent dose
             orally  administered  (Poiger and  Schlatter,  1980).

             Inhalation absorption of 2,3,7,8-TCDD has not been studied (U.S. EPA,

             Diamond Shamrock  (1985)  noted greater oral  absorption  of  2,3,7,8-
             TCDD in animals  given contaminated soil containing oil than  without
             In  the Poiger and Schlatter  (1986) study, concentrations of  3.0 and
             2.8 ppt  of  3H-2,3,7,8-TCDD were detected in adipose tissue 10 and 69
             days, respectively, after treatment.

2,3,7,8-Tetrachlorodibenzo-p-Dioxin                          March 31,  1987

       0  Tissue distribution following oral or intraperitoneal  (i.p.)  admini-
          stration of 2,3,7,8-TCDD to rats  appears  to be  preferentially to the
          liver and adipose tissue (Fries and Marrow,  1975;  Rose et al.,  1976;
          Van Miller et al.,  1976; Kociba et al.,  1978).   Other  tissues showed
          substantially lower concentrations of 2,3,7,8-TCDD.  Soon after treat-
          ment, the liver may have concentrations about three  (Kociba et al.,
          1978a) to five (Rose et al.,  1976) times  that in adipose  tissue.
          It was suggested that male rats accumulate  2,3,7,8-TCDD in the liver
          more efficiently than female  rats (Fries  and Marrow, 1975).  Tissue
          distribution in mice (Manara  et al., 1982)  and  hamsters (Olson
          et al.,  1980a) seems to be similar to that  in rats.

       0  Monkeys,  however,  appear to accumulate 2,3,7,8-TCDD preferentially
          in adipose tissue to a greater extent than  in the  liver (Van  Miller
          et al.,  1976; McNulty et al.,  1982).  Two years after  a single oral
          dose to a monkey,  adipose tissue  contained  100  ppt and the liver 15
          ppt 2,3,7,8-TCDD (McNulty et  al., 1982).  Prolonged tissue retention
          of the compound was thus demonstrated. Tissue  distribution in guinea
          pigs appears to be  similar to that in monkeys (Gasiewicz  and  Neal,
          1979; Nolan et al., 1979)  since tissue levels in adipose  tissue
          exceed those in the liver.

       0  Evidence that 2,3,7,8-TCDD accumulates in the adipose  tissue  of
          exposed humans was  presented  by Young et  al. (1983) who reported
          levels of 3 to 99 ppt in the  adipose tissue.of  armed forces veterans
          claiming health problems related  to Agent Orange.

       0  Fetal distribution  of 2,3,7,8-TCDD has been studied in rats (Moore
          et al.,  1976) and mice (Nau and Bass, 1981;  Nau et al., 1982).
          Levels of 2,3,7,8-TCDD were low in rat fetuses  on  gestation days 14
          and 18 of gestation and appeared  to be evenly distributed in  all fetal
          tissues.   On day 21 of gestation, the fetal liver  showed  a marked
          affinity for 2,3,7,8-TCDD (Moore  et al.,  1976).  2,3,7,8-TCDD was
          distributed to the fetuses of mice following oral, i.p. or subcu-
          taneous (s.c.) administration (Nau et al.,  1982).  Maximum fetal
          concentrations occurred on days 9 and 10  of gestation; lower  fetal
          concentrations were observed  on gestation days  11  through 18, coinci-
          dent with placentation.  The  fetal liver  had less  affinity for the
          compound than did the maternal liver.

       0  Ryan et al. (1985)  reported 2,3,7,8-TCDD  levels of 5-10 ppt in
          adipose tissue samples from humans taken  at autopsy across Canada.
          Higher levels of other dioxins were also  found.


       0  In an early metabolism study,  Vinopal and Casida (1973) reported that
          in vivo or in vitro studies with  mice showed that  polar metabolites
          of 2,3,7,8-TCDD were not produced by this species.  In rats,  however,
          hydroxylation and conjugation with glucuronide  and sulfate have been
          demonstrated (Poiger and Schlatter, 1979; Poiger et al.,  1982;
          Olson et al., 1983).  Glucuronide conjugates tended to predominate
          in the bile (Poiger and Schlatter, 1979)  and sulfate conjugates were
          located in the urine (Olson et al., 1983).

2,3,7,8-Tetrachlorodibenzo-p-Dioxin                          March 31,  1987

          Poiger and Schlatter (1979)  stated that metabolism of 2,3,7,8-TCDD
          proceeds slowly in the liver.   Neal et al.  (1982)  demonstrated
          that the rate of hepatic metabolism was enhanced by activated cyto-
          chrome P-450 raono-oxygenase.  It was suggested that metabolism of
          2,3,7,8-TCDD proceeds  by the formation of reactive epoxide intermedi-
          ates (Poland and Glover, 1979).  Dechlorination also was demonstrated
          by Olson et al. (1983) and Sawahata et al.  (1982), who identified
          tri- and dichlorodibenzo-p_-dioxins as metabolites  in in vitro rat
          hepatocyte systems.  From the  bile of dogs,  six major metabolites
          have been identified (Poiger et al., 1982);  hydroxylated conjugates
          of tetra-,  tri- and  dichlorodibenzo-p_-dioxin predominated.

          Although metabolite  profiles are consistent  with an arene oxide
          intermediate,  the covalent interaction of 2,3,7,8-TCDD with cellular
          macromolecules is minimal.
       0   When  the  excretion  data  are  plotted  send-logarithmically,  a  straight
          line  results,  suggesting that elimination of  2,3,7,8-TCDD  is a first-
          order phenomenon, especially in  rats.   Excretion  in  the  guinea pig
          may be  a  zero-order process  (Gasiewicz  and Neal,  1979).  The half-life
          for body  elimination varied  considerably  with estimated  ranges of 10
          to  15 days  in  the hamster (Olson et  al.,  1980a),  the species least
          sensitive to the toxic effects of 2,3,7,8-TCDD,  11 to 24 days in the
          mouse (Gasiewicz et al.,  1983a,b), 17 to  31 days  in  the  rat  (Piper,
          et  al.,  1973;  Allen et al.,  1975; Rose  et al.,  1976) and 22  to 30
          days  in the guinea  pig  (Gasiewicz and Neal, 1979; Nolan  et al.,
          1979).  One strain  of mice,  DBA/2J,  had a half-life  for  elimination
          of  approximately 24 days,  about  twice as  long as  in  other  strains
          tested  by Gasiewicz et al. (1983a,b).   These  authors also  noted that
          this  strain of mice had  a greater tendency to accumulate 2,3,7,8-TCDD
          in  adipose  tissue than did other strains  and  that this phenomenon
          probably  resulted in slower  body elimination.  Half-lives  for body
          elimination of 2,3,7,8-TCDD  have not been calculated for the monkey,
          but it  was  suggested that the tendency  of this  species to  accumulate
          2,3,7,8-TCDD in adipose  tissue may also result  in slow body  elimination
          (Van  Miller et al.,  1976).

       0   Recently, Olson and Bittner  (1983) examined the elimination  of 2,3,7,8-
          TCDD  in rats over a longer period than  in the studies previously
          summarized  and determined  that biphasic elimination  occurred.   They
          estimated a half-life of  approximately  7  days for the initial rapid
          phase and a half-life of  approximately  75 days  for the slower phase,
          probably  related to release  from stores of body fat. McNulty et al.
          (1982)  estimated the half-life for elimination  from  the  fat  of monkeys
          to  be approximately 1 year.

       8   In  the  Poiger  and Schlatter  (1986) study,  11.5% of the 3H-TCDD was
          excreted  in feces during  the first three  days after  treatment,  and
          no  3u activity was  found in  urine.   These investigators  estimated an
          elimination half-life of 4.95 years  for the 3n-TCDD.

  2,3,7,8-Tetrachlorodibenzo-p-Dioxin                          March 31,  1987


         0  The fecal route seems to be the major pathway for the elimination of
            2,3,7,8-TCDD-derived radioactivity in rats (Piper et al.,  1973;
            Allen et al.,  1975;  Rose et al.,  1976; Van Miller et al.,  1976),
            guinea pigs (Gasiewicz and Neal,  1979) and mice (Gasiewicz et al.,
            1983a,b).  Urinary excretion played less of a role in these species,
            accounting for <1  to 28% of total excreted radioactivity while fecal
            excretion accounted for 72 to >99% of the eliminated radioactivity.
            Urinary excretion  accounted for a more substantial proportion of  body
            elimination in hamsters (41% as compared with 59% by feces) (Olson,
            et al., 1980a) and that strain of mice (DBA/2J) which preferentially
            accumulated 2,3,7,8-TCDD in body  fat (Gasiewicz et al.,  1983a,b).

         0  The failurb to detect metabolites of 2,3,7,8-TCDD in liver and fat
            (Olson et al., 1983) indicates that elimination of the metabolites
            occurs rapidly and that the rate  of elimination is governed primarily
            by the rate of hepatic metabolism.

            Either acute or chronic exposure to 2,3,7,8-TCDD (usually  in combi-
            nation with other substances)  may result in chloracne,  altered liver
            function,  hematological lesions,  porphyria cutanea tarda,  hyperpig-
            mentation, hirsutism and neural degeneration in the extremities (U.S.
            EPA,  1985a).  Stevens (1981) has estimated that the minimum cumulative
            toxic dose of 2,3,7,8-TCDD in  humans is 0.1  ug/kg.

            Rowe  (1968) has described experiments showing a dose-response for
           -chloracne  in humans acutely exposed to topical applications of

            The toxic  effects of chloracne from exposure to 2,3,7,8-TCDD may
            persist for many years, though other effects noted in various
            individuals are apparently reversible after a short period.  Epidemio-
            logical studies have failed to demonstrate a convincing connection
            between 2,3,7,8-TCDD exposure  and spontaneous abortions or malfor-
            mations in humans.  Some evidence of cytogenetic damage has been
            reported in humans exposed to  chemicals contaminated with  2,3,7,8-TCDD,
            but negative results have also been reported; exposures were not
            quantitated and the other chemicals cannot be ruled out as causative
            agents (U.S. EPA, 1985a).

            Swedish case-control studies provide limited evidence for  the carcino-
            genicity of phenoxy acids or chlorophenols or both in humans.  However,
            with respect to the dioxin impurities contained within them, the evidence
            for the human carcinogenicity  for 2,3,7,8-TCDD based on epidemiologic
            studies is only suggestive because of the difficulty of evaluating
            the risk of 2,3,7,8-TCDD exposure in the presence of the confounding
            effects of phenoxy acids and/or chlorophenol (U.S. EPA, 1985a).

2, 3, 7,8-Tetrachlorodibenzo-p-Dioxin                          March 31, 1987



  Short-term Exposure

       0  There are wide variations in species sensitivity to the acute toxicity
          of 2, 3, 7, 8-TCDD.   LDsgs range from 0.6 ug/kg for the male guinea pig
          to >5,000 ugAg bw for the male hamster (Schwetz et al., 1973; Olson,
          et al.,  1980b;  Henck et al.,  1981).  The toxic manifestations seem
          to be the same  whether the compound is given as a single oral dose or
          as a limited number of multiple treatments,  with death occurring from
          5 to 45  days post-treatment.   Lethal exposures result in weight loss,
          often described as "wasting away" and thymic atrophy.  In some species,
          particularly rats  and mice,  extensive liver  damage is observed (Gupta
          et al.,  1973).   In general,  no specific cause of death has been
          identified,  although extensive hemorrhaging  has been implicated in
          mice (Vos et al.,  1974).

       0  In rats,  single high doses (200 ug/kg)  produce liver necrosis (Jones
          and Butler,  1974),  while  lower doses (5 and  25 ug/kg) result in fatty
          changes  in the  liver and  proliferation of the endoplasmic reticulum
          (Fowler  et al., 1973). Other effects seen in some species include
          induction of microsomal enzymes, degeneration of plasma membranes
          with loss of ATPase activity,  a decreased ability to excrete some
          xenobiotics  in  the bile,  porphyria, altered  gastrointestinal absorption
          of some  nutrients  and decreased blood cellularity (U.S. EPA, 1985a).
          Turner and Collins' (1983) found treatment-related liver lesions in
          guinea pigs  given  single  gavage doses of 2, 3, 7, 8-TCDD at 0.1 ugAg
          and higher.

       8  2, 3, 7, 8-TCDD is an immunotoxin in laboratory animals, predominantly
          affecting cell-mediated immunity.  Hypers ens itivity, adverse effeofes-—
          on the thymus and  increased  sensitivity to antigens have demonstrated
          the immunotoxic potential of  2, 3, 7, 8-TCDD.  Weanling rodents show
          greater  susceptibility to immune effects compared to adults (U.S.
          EPA,  1985a).

  Long-term Exposure

       0  In rats  and  mice,  the liver appears to be the most sensitive organ
          following chronic  or subchronic exposure. Hepatotoxicity develops
          following a  long induction period and the changes persist for long
          periods  following  the termination of exposure (King and Roesler,
          1974;  Goldstein et al., 1982).

       0  Liver lesions as well as  other toxic signs were observed in the
          following studies  in rats and  mice.   In the  subchronic studies, the
          NOAEL of  0.01 ugAg/day (Kociba et al.,  1976)  and 0.5 ugAg/week
          (NTP,  1980)  have been reported for rats.   A  NOAEL of 2 ugAg/week was
          identified for  female mice and a LOAEL of 1  ugAg/week for male mice
          in the NTP (1980)  subchronic study.   A NOAEL of 0.001  ugAg bw/day,  a
          LOAEL of  0.01 ugAg/day,  and an effect  level of 0.1  ugAg/day have
          been  reported for  rats following chronic dietary exposure (Kociba
          et al.,  1978a,b, 1979;  NTP, 1980).  Toth et  al.  (1978,  1979)  observed

2,3,7,8-Tetrachlorodibenzo-p-Dioxin                          March 31,  1987

          toxic effects in mice at doses as low as  0.007 ug/kg/week given for
          one year by gavage.   Gavage dosing for two years  led to toxic hepatitis
          at a NOAEL of 0.05 ug/kg/week and a LOAEL of  0.5  ugAg/week in rats,
          a LOAEL of 0.5 ug/kg/week in male mice, and a LOAEL of 2.0 ugAg/week
          in female mice (NTP,  1980).

       0  DeCaprio et al.  (1986)  fed 2,3,7,8-TCDD in the diet for 90 days to
          male and female Hartley guinea pigs,  and  found SCAELs of 0.12 and
          0.61 (male) and 0.68  (female) mg/kg/day;  decreased body weight gain,
          increased relative liver weights, decreased relative thymus weights,
          and hepatocellular cytoplasmic inclusion  bodies at 4.90 (males) and
          4.86 (females) mg/kg/day;  and,  mortality  and  other mentioned effects
          at 26 (males) and 31  (females)

  Reproductive Effects

       0  Adverse effects  of 2,3,7,8-TCDD on reproduction in rats exposed
          through the diet were observed  by Murray  et al. (1979) and are
          detailed under Lifetime Health  Advisory.

  Developmental Effects

       0  2,3,7,8-TCDD has been demonstrated to be  teratogenic in mice.   The most
          common malformations  observed are cleft palate and kidney anomalies;
          however,  other malformations have'been observed occasionally.   With an
          effect level of  1  ugAg/day, 2,3,7,8-TCDD is  the  most potent teratogen
          known.  At higher doses,  2,3,7,8-TCDD has a marked fetotoxic effect,
          as measured by decreased fetal  weight and increased fetal toxicity.
          Hemorrhagic GI tract  has  been associated  with 2,3,7,8-TCDD fetal
          toxicity .(U.S. EPA, 1985a).

       0  Poland and Glover (1980)  produced evidence that responsiveness of
          mice to cleft palate  from 2,3,7,8-TCDD treatment  is related to the
          presence of Ah receptor.

       0  In rats,  it has  also  been consistently observed that 2,3,7,8-TCDD
          produces fetotoxic responses.  In this species, the most common fetal
          anomalies observed were edema,  hemorrhage and malformation of  the
          kidney with effects observed at doses of  *0.01  ugAg/day.  In
          addition, there  is some evidence that 2,3,7,8-TCDD can induce  micro-
          somal enzymes in the  fetus exposed in utero,  and  this induction is
          accompanied by damage to the fine structure of the liver cell; however,
          other reports indicate  that enzyme induction  occurs only after birth
          following exposure to 2,3,7,8-TCDD through the mother's milk.   As in
          mice, hemorrhagic GI  tracts have been observed in rat fetuses  exposed
          in utero to 2,3,7,8-TCDD (U.S.  EPA, 1985a).

       0  Rabbits and monkeys are also susceptible  to the fetotoxic effects of
          2,3,7,8-TCDD; however,  the studies of these species have been  too
          limited to clearly demonstrate  a teratogenic  response or define a
          threshold dose for fetotoxicity (U.S. EPA, 1985a).

  2,3,7,8-Tetrachlorodibenzo-p-Dioxin                          March  31,  1987



         °  In vivo and in vitro mutagenicity tests have produced inconclusive
           evidence as to the mutagenicity of TCDD (U.S. EPA, 1985a).

         0  Early reports indicated that 2,3,7,8-TCDD was mutagenic in S_. typhi-
           murium strain TA1532 (Hussain et al., 1972; Seiler, 1973); however,
           later attempts to confirm these results have been unsuccessful  (Nebert,
           et al., 1976; McCann, 1978; Gilbert et al., 1980; Geiger  and  Neal,
           1981).  2,3,7,8-TCDD has been reported to be mutagenic to 12.  coli in
           vitro (Hussain et al., 1972) and to S_. cerevisiae in vitro, and in a
           host-mediated assay (Bronzetti et al., 1983).  Covalent interactions
           with nucleic acids are minimal if they occur at all (Kondorosi et al.,
           1973; Poland and Glover,  1979).  Only marginal effects have been
           observed on the incidence of chromosomal aberrations in vivo  (Green
           and Moreland,  1975).  A test for unscheduled DNA synthesis in cultured
           male rat hepatocytes was negative (Althaus et al., 1982).  Loprieno
           et al. (1982)  reported 2,3,7,8-TCDD as clastogenic in mice in vivo,
           negative for cytogenetic effects in vivo, and negative for unscheduled
           DNA synthesis in a human cell live in vitro.  Hay (1983) reported
           2,3,7,8-TCDD as mutagenic in the baby hamster kidney cell transfor-
           mation assay.

   Carcinogenici ty

         0  Several bioassays have demonstrated this compound to be a potent
           carcinogen in rats and mice (Kbciba et al., 1978a; Toth et al., 1979;
           NTP, 1980).  Adenomas or carcinomas of the thyroid,  hepatocellular
           carcinomas, carcinomas of the tongue and hard palate,  and adenomas of
           the adrenal gland have been induced in rats and mice.

         0  Significant (P <0.05) neoplastic effects were evident at dietary
           levels of 0.01 and 0.1  ug/kg/day but not at 0.001 ug/kg/day in the
           two-year study with Sprague-Dawley rats by Kociba et al.  (1978).  In
           Osborne-Mendel rats given 2,3,7,8-TCDD in corn oil:acetone twice
           weekly for total weekly doses of 0.01, 0.05 and 0.5 ugAg/week for
           two years, significant (P <0.05) tumor increases were thyroid in mid-
           and high-dose  males and liver in high-dose males (NTP,  1980).  In the
           NTP O980) study in which B6C3F1 mice were dosed like the rats except
           that females received 0.04,  0.2 and 2.0 ug/kg/week,  significant
           (P <0.05)  tumor increases were in liver in high-dose males and females
           and thyroid in high-dose  males.


        Health Advisories (HAs)  are  generally determined  for One-day, Ten-day,
   Longer-term (approximately 7 years)  and Lifetime exposures if  adequate data
   are available that identify a sensitive noncarcinogenic end  point of toxicity.
   The HAs for noncarcinogenic toxicants are derived using the  following formula:

                 HA = (NOAEL or LOAEL)  x (BW) = 	 mg/L  (	 u /L)
                        (UF) x (     L/day)

2,3,7,8-Tetrachlorodibenzo-p-Dioxin                          March  31,  1987


          NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
                           in mgAg bw/day.

                      BW * assumed body weight of  a child (10 kg)  or
                           an adult (70 kg).

                      UF = uncertainty ;actor (10,  100 or 1,000),  in
                           accordance with NAS/ODW guidelines.

               _____ L/day = assumed daily water consumption of a child
                           (1  L/day)  or an adult (2 L/day).

  One-day Health Advisory

       Turner and Collins (1983)  administered single oral doses of 2,3,7,8-TCDD
  at 0.1, 0.5,  2.5, 12.5 or 20 ugAg in aqueous methyl cellulose to groups of
  4 to 7 female guinea pigs.  Survivors were  killed 42 days after dosing and
  examined for histopathologic changes in the liver.  Four of the 7 animals in
  the highest dose group and 1 of 5 in the 12.5 ug/kg group died before the end
  of the observation period.  Mild histopathologic changes, including steatosis
  (fatty change), focal necrosis  and cytoplasmic degeneration were noted in
  animals from all treated groups, but not in controls.  The authors indicated
  that quantitative differences among the dosage groups were not detectable by
  light microscopy.

       A LOAEL of 0.1 ug/kg can be derived from the study of Turner and Collins
  (1983) for calculating a One-day HA, using  an uncertainty factor (UF) of 1,000
  for an animal LOAEL.  This UF consists of two 10-fold factors to account for
  both intra- and interspecies variability to the toxicity of this chemical in
  the absence of chemical-specific data, and  an additional 10-fold factor
  because the HA is based on a LOAEL and not  a NOAEL.

       For a 10-kg child consuming 1  L of drinking water per day,  the One-day
  HA is calculated as follows:

                  One-day HA - (0.1 ugA
 2,3,7,8-Tetrachlorodibenzo-p-Dioxin                            March  31,  1987


 Ten-day  Health Advisory

      Because of  the demonstrated sensitivity of  the guinea pig to  acute
 toxicity of 2,3,7,8-TCDD, the Ten-day HA is derived by dividing  the One-day
 HA by ten.  The  Ten-day HA is, therefore, 0.0001 ug/L.

 Longer-term Health Advisory

      The three-generation reproduction study in  rats by Murray et  al.  (1979)
 has been selected because the animals in this study were administered  2,3,7,8-
 TCDD  by  diet on  a daily basis for an  appropriate duration as opposed to the
 gavage method of treatment used in other studies considered and  because the
 adverse  effect was on reproduction.   Comparison with the other studies in
 which different  treatment protocols were used suggests that the  dose of
 0.001 ugAg/day, concluded by the U.S. EPA as a LOAEL for adverse  effects
 on the pups and  dams in the Murray et al. (1979) study would be  protective
 against  the toxic effects found in the other studies.  Although  DeCaprio
 et al. (1986) found NOAELs of 0.61 and 0.68 ng/kg/day in their 90-day guinea
 pig study, this  dose is slightly below the LOAEL of 0.001 ugAg/day
 (1 ng/kg/day) in another species which, in turn, is below the LOAEL of
 4.86  ng/kg/day in the DeCaprio et al. (1986) study.

      Using an uncertainty factor of 1,000 for an animal LOAEL (i.e., 10-fold
 for intra- and 10-fold for interspecies variability to the toxicity of a
 chemical in the absence of specific data, and an additional 10-fold factor
 because  the estimate is based on a LOAEL rather than a NOAEL), a Longer-term
 HA can be calculated from the LOAEL of 0.001 ugAg/day concluded for the
 Murray et al. (1979) study.

      For a 10-kg child consuming 1 L of drinking water each day,  the Longer-
 term  HA  is calculated as follows:

          Longer-term HA » (0.001 ugAg/day) (10 kg) = 0.00001 ug/L
                               (1,000) (1 L/day)


         0.001  ugAg/day - LOAEL from study by Murray et al. (1979).

                 * 10 kg • assumed weight of child

                  1,000 = uncertainty factor,  chosen in accordance with NAS/ODW
                          guidelines for use with a LOAEL from an animal study.

                1 L/day = assumed daily water consumption of a child.

     By substituting 70-kg body weight and daily consumption of 2L of  water
 for the adult in the above equation,  the Longer-term HA for the 70-kg  adult
becomes 0.000035 ug/L.

2,3,7,8-Tetrachlorodibenzo-p-Dioxin                           March  31,  1987


  Lifetime Health Advisory                      *                *

       The Lifetime  HA represents  that  portion  of  an  individual's total exposure
  that is  attributed to drinking water  and is considered  protective of  noncar-
  cinogenic adverse  health effects over a  lifetime exposure.   The Lifetime  HA
  is  derived in  a three step process.   Step 1 determines  the  Reference  Dose
  (RfD), formerly called the Acceptable Daily Intake  (ADI).   The RfD is an  esti-
  mate of  a daily exposure to  the  human population that is  likely to be without
  appreciable risk of deleterious  effects  over  a lifetime,  and is derived from
  the NOAEL (or  LOAEL), identified from a  chronic  (or subchronic) study,  divided
  by  an uncertainty  factor(s).   From the RfD, a Drinking  Water Equivalent Level
  (DWEL) can be  determined (Step 2).  A DWEL is a  medium-specific (i.e.,  drinking
  water) lifetime exposure level,  assuming 100% exposure  from that  medium,  at
  which adverse,  noncarcinogenic health effects would not be  expected to  occur.
  The DWEL is derived from the multiplication of the  RfD  by the assumed body
  weight of an adult and divided by the assumed daily water consumption of  an
  adult.   The Lifetime HA is determined in Step 3  by  factoring in other sources
  of  exposure, the relative source contribution (RSC).  The RSC from drinking
  water is based on  actual exposure data or, if data  are  not  available, a
  value of 20% is assumed for  synthetic organic chemicals and a value of  10%
  is  assumed for inorganic chemicals.   If  the contaminant is  classified as  a
  Group A  or B carcinogen, according to the Agency's  classification scheme  of
  carcinogenic .potential (U.S. EPA, 1986),  then caution should be exercised in
  assessing the  risks associated with lifetime  exposure to  this chemical.

       The EPA has developed for comparison with cancer-based criteria, a pre-
  sumed safe daily intake level  based on noncarcinogenic  effects as indicated
  in  U.S.  EPA (1984b).  For consistency, the rationale used by EPA  for  the
  calculation of this value in U.S. EPA (1984b) is used here  for the DWEL
  calculation.   The  rationale  as presented in U.S. EPA  (1984b)  is as follows:
            2,3,7,8-TCDD displays an  unusually high degree  of  reproductive
       toxicity.   It is  teratogenic,  fetotoxic and reduces  fertility.   In  a
       3-generation reproductive study,  Murray et al.  (1979) reported  a
       reduction  in fertility  after daily dosing  at 0.1  or  0.01 ug  2,3,7,8-
       TCDD/kg in the FI and F2 generations  of Sprague-Dawley  rats.  Although
       Murray  et  al. (1979) considered  the lowest dose  tested,  0.001 ug/kg»
       to be a no-observed-effect level (NOEL), a re-evaluation of  these data
       by Nisbet  and Paxton  (1982), using different statistical methods,
       indicated  that there was a reduction  in the gestation index,  decreased
       fetal weight, increased liver  to body weight ratio,  and increased
       incidence  of dilated renal pelvis at  the 0.001 ugAg dose.   The
       reevaluated data  would  suggest that equivocal adverse effects were
       seen at the lowest  dose (0.001 ug/kg/day)  and that this dose  should,
       therefore, represent a  lowest-observed-adverse-effect level  (LOAEL).
       Schantz et al. (1979) found reductions in  fertility  and various other
       toxic effects in  rhesus monkeys  fed a 50 ppt 2,3,7,8-TCDD diet  for
       20 months.  This  corresponds to  a calculated daily dose of 0.0015 ug
       2,3,7,8-TCDD/kg/day.  These results suggest that monkeys may be
       somewhat more sensitive than rats, since the effects in monkeys were
       more severe and not equivocal.   Since the  data  from  the limited study by
       Schantz et al. (1979) are supportive  of the findings by Murray  et al.
       (1979)  it  seems reasonable to  determine an ADI  based on the  LOAEL.

2,3,7,8-Tetrachlorodibenzo-p-Dioxin                          March 31,  1987

       From these results,  a LOAEL of 0.001  ug/kg was  identified.   Using this
  LOAEL,  the DWEL is  derived as  follows:

  Step 1:   Determination of the  Reference  Dose (RfD)

                  RfD = (0.001 ug/kg/day)  =  ,  x 10-6 ug/kg/day


          0.001  ug/kg/day = LOAEL.

                    1,000 = uncertainty factor,  chosen in accordance with NAS/ODW
                            guidelines for use with a  LOAEL from an animal study.

  Step 2:   Determination of the  Drinking Water Equivalent Level (DWEL)

               DWEL = (1 * 10-6  ug/kg/day) (70 kg) = 0.000035 ug/L
                             (2  L/ day)


          1 x 10-6 ug/kg/day = RfD.

                       70 kg = assumed body  weight of  an adult.

                    2 L/ day = assumed daily water consumption of an adult.

       2,3,7,8-TCDD is placed in Group B:   Probable human carcinogen.  The
  estimated excess cancer risk associated  with lifetime exposure to drinking
  water co'ntaining 2,3,7,8-TCDD  at 3.5 x 1 0~5 ug/L is  approximately 2 x 10~4.
  This estimate represents the upper 95% confidence limit from extrapolations
  prepared by EPA's Carcinogen Assessment  Group using  the linearized, multistage
  model.  The actual  risk is unlikely to exceed this value, but there is
  considerable uncertainty as to the accuracy of risks calculated by this

  Evaluation of Carcinogenic Potential

       0  Cancer potency estimates were derived using  the multistage model and
          the tumor data on female rats in the chronic feeding study by Kociba
          et al. (1978a) (U.S. EPA, 1985a,b).

       0  The 95% upper-limit carcinogenic potency factor for humans, q-)*, is
          1.56 x 105  (mg/kg/day)-1.  For a 70 kg human drinking 2 L water/day,
          the water concentration should be  2.2 x 10~6 ug/L in order to keep
          the upper-limit individual lifetime cancer risk at 10-5.  Water
          concentrations corresponding to  excess cancer risk of 10-4 and 10-6
          are, therefore, 2.2 x  10-5 and 2.2 x 10~7 ug/L, respectively.

       0  Maximum likelihood estimates as  well as 95%  upper limits of cancer
          risks by the multistage model have been calculated (U.S. EPA, 1985b).
          For example, at 1 x 10~3 ng/kg/day or 0.035  ng/L cancer risk estimates

  2,3,7,8-Tetrachlorodibenzo-p-Dioxin                          March 31,  1987


            are 1.1 x 1CT4 (MLE) and 1.5 x 1CT4 (UL) and at 1 x 10~2 ngAg/day
            cancer risk estimates are 1.1 x 10~3 (MLE) and 1.5 x 10~3 (UL).

         0  The EPA's Carcinogen Assessment Group has estimated cancer risks with
            other models besides the multistage (U.S. EPA, 1985b).   As an example,
            1 x 10~3 ngAg/day lifetime exposure was associated with additional
            risks (95% upper confidence limit) of 1.5 x 10"4 by the multistage
            and one-hit, 2.9 x 1CT3 by the Weibull,  and 7.5 x 1CT8 by the log-
            probit, using the Kociba analysis of the data.  While recognized as
            statistically alternative approaches, the range of risks described by
            using any of these modeling approaches has little biological signifi-
            cance unless data can be used to support the selection of one model
            over another.  In the interest of consistency of approach and in
            providing an upper bound on the potential cancer risk,  the EPA has
            recommended use of the linearized multistage approach.

         8  The IARC (1981) classified TCDD as a 2B chemical (sufficient animal
            evidence; inadequate human evidence) for carcinogenicity.

         8  Applying the criteria described in EPA's guidelines for assessment of
            carcinogenic risk (U.S. EPA, 1986), 2,3,7,8-TCDD maybe classified in
            Group B2:  Probable human carcinogen.  This category is for agents for
            which there is inadequate evidence from human studies and sufficient
            evidence from animal studies.


         0  For 2,3,7,8-TCDD, the U.S. EPA has established criteria of 1.3 x 1CT7,
            1.3 x 10~° or 1.3 x 10~9 ug/L in ambient waters, based on an assumed
            daily consumption of 6.5 g of contaminated fish and shellfish and 2 L
            of drinking water (U.S. EPA, 1984b).  Under these conditions, 94.2%
            of the total exposure would result from the consumption of aquatic
            organisms.  The recommended levels correspond to estimated human
            lifetime excess cancer risks of 10~5, 10~° or 1CT7, respectively.
            These values are considerably lower than the HAs for drinking water,
            reflecting the high bicaccumulation potential of this compound in
            aquatic species.

         8  The FDA advises that fish containing >50 ppt of 2,3,7,8-TCDD should
            not be consumed and those containing >25 ppt, but <50 ppt, should not
            be consumed more than twice a month (FDA, 1983).  This is reflected
            in a Canadian limit of 20 ppt in the Lake Ontario commercial fish
            imported into the United States (NKCC, 1981).

         0  An ADI of 1CT4 ug/kg bw/day has been proposed previously for 2,3,7,8-
            TCDD by the National Academy of Sciences Safe Drinking Water Committee
            (NAS, 1977).  This ADI was based on a 13-week rat feeding study by
            Kociba et al. (1976) and was proposed before convincing evidence for
            the carcinogenicity of 2,3,7,8-TCDD had accumulated.

    2,3,7,8-Tetrachlorodibenzo-p-Dioxin                          March 31, 1987



           0  Determination of dioxin is by a gas chromatographic/mass spectrometer
              (GC-MS) method (Method 613.  U.S. EPA, 1984c).  In this method, a one
              liter sample is spiked with an internal standard of a labeled dioxin
              and extracted with methylene chloride using a separatory funnel.  The
              methylene chloride extract is exchanged to hexane during concentration
              to a volume pf approximately 1 mL.  The extract is then analyzed by
              capillary column GC/MS to separate and measure dioxin.  The method
              detection limit is dependent upon the nature of interferences, but it
              is estimated to be about 0.02 ug/L.


           0  Because of its high toxicity and low potential for occurrence in
              drinking water, very little information is available on the removal
              of dioxins from drinking water.   Granular activated carbon adsorption
              is likely to be the most reasonable treatment approach and the small
              amount of empirical evidence available bears this out.

           0  While looking for a method to concentrate polychlorinated dibenzo-p-
              dioxins and dibenzofurans,  scientists from the U.S. Fish and Wildlife
              Service's fish-pesticide research laboratory in Columbia,  Missouri,
              found that TCDD is extremely difficult to recover from GAC once it
              has been adsorbed (Chemical Engineering and News, 1977).  Subsequent
             . pilot-scale tests of carbon adsorption of Agent Orange [50-50 mixture
              of the acid esters of 2,4,5-T and 2,4-dichlorophenoxyacetic acid
              (2,4-D)] reduced an initial concentration of 10 mg/L dioxin in the
              herbicide to a final concentration of less than 0.1  mg/L.   Details of
              the adsorption test were not reported by the authors.  Based on these
              data and the reported low water  solubility of 0.2 ug/L dioxin in
              water (Bollen and Norris, 1979), it appears that GAC adsorption of
              dioxin from water is potentially feasible.

  2,3,7,8-Tetrachlorodibenzo-p-Dioxin                          March  31,  1987



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2,3,7,8-Tetrachlorodibenzo-p-Dioxin                          March 31,  1987

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