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RegulatorySCIENCEDIRECTreg Toxicology and Pharmacology

Regulatory Toxicology and Pharmacology 42 (2005) 161-171

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Health effects classification and its role in the derivation of minimal risk levels Hepatic effects

Hana R Pohl C-H Selene 1 Chou

Agency for Toxic Substances and Disease Registry us Department of Health and Human Services Atlanta GA 30333 USA

Received 8 December 2004 A vailable online 24 May 2005

Abstract

The Agency for Toxic Substances and Disease Registry (ATSDR) derives health based guidance values called minimal risk levels (MRLs) to assist with assessment of risks posed by exposures to hazardous chemicals Current MRLs are posted on ATSDRs web site (wwwatsdrcdcgov) From the total 326 MRLs currently posted 79 MRLs are based on hepatic endpoints The paper reports on endpoints used for the derivation of these MRLs and the use of uncertainty factors It also describes the ranking of effects into less serious and serious categories as described in ATSDRs Gllidanceor Developing Toxicological Profiles Published by Elsevier Inc

Keywords Hepatic effects Health guidance values MRL RfC RID

1 Introduction

Over 600 drugs and numerous environmental chemishycals have demonstrated toxicity to the liver in humans or in laboratory animals (Evans and Lake 1998) The liver is a target organ for toxic chemicals because of its posishytion in the organism metabolic capabilities and secreshytory and excretory functions Chemicals that enter the organism by oral route first traverse the hepatic portal system before reaching the systemic circulation Metaboshylism may change the toxicity (active or inactive metaboshylites) or the bioavailability (first-pass effect) of the parent

middot4 chemicals (Bryson 1997) In fact most chemicals feashytured in ATSDRs toxicological profiles display some hepatotoxic effects However hepatotoxicity was the most sensitive target endpoint for only 53 chemicals Identifying the most sensitive endpoint is important for ATSDR to derive the health-based guidance values minshyimal risk levels (MRLs) An MRL is defined as an estishymate of the daily human exposure to a substance that is

Corresponding author Fax + I 770488 4178 E-mail address hpohlcdcgov (HR Pohl)

I 0273-23001$ - see front matter Published by Elsevier Inc doi 1010 16jyrtph2005D3002

likely to be without an appreciable risk of adverse nonshycancer effects over a specified duration of exposure (ATSDR 1992 1996a) ATSDR uses MRLs as a screenshying tool for evaluation of chemicals around hazardous waste sites and their possible impact on human populashytions living in the vicinity of the sites

The purpose of this paper is to inform the public about MRLs based on hepatobiliary effects and about the guidshyance provided for the sections of toxicological profiles describing these health effects and their categorization in ATSDRs Guidance for Developing Toxicological Profiles (ATSDR 1996b 2003) So far the guidance has served as an internal document However parts of the guidance related to neurological developmental hematological and respiratory effects and the respective MRLs were preshyviously published (Abadin et aI 1998 Chou and Wilshyliams-Johnson 1998 Pohl et aI 1998 Wilbur 1998)

2 Materials and methods

By Congressional mandate ATSDR develops toxicoshylogical profiles for hazardous substances found at

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162 HR Pohl c-H Sl Chou I Regulatory Toxicology and Pharmacology 42 (2005) 161-171 HR Poh c-HSJ Chou I Regulatory Toxicology and Pharmacology 42 (2005) 161-171 171

National Priority List (NPL) sites ATSDR also preshypares toxicological profiles for the Department of Defense (DOD) and the Department of Energy (DOE) on substances related to federal sites So far about 250 profiles were published as final documents The profiles focus on health and toxicological information Toxicoshylogical profiles (final and draft documents) can be found on ATSDRs web site (wwwatsdrcdcgov) MRLs are an integral part of the toxicological profiles

MRLs are derived according to current ATSDR methshyodology (Chou et aI 1998 Pohl and Abadin 1995) ATSDR uses the highest no-observed-adverse-effect level (NOAEL) or lowest low-observed-adverse-effect level (LOAEL) in the available literature to derive the MRLs Proper categorization of health effects is therefore critical for the MRL derivation The 79 MRLs related to hepatoshytoxicity were based on vast databases compiled in the 53 toxicological profiles for the respective chemicals A list of all current MRLs (updated on May 112004) is available on ATSDRs web site (wwwatsdrcdcgov)

3 Results and discussion

31 A TSDRs health effects classification

To determine the levels of significant human exposure to a given chemical and associated health effects ATSDRs toxicological profiles examine and interpret available toxicological and epidemiological data As described in the preceding papers (Chou et aI 1998 Pohl and Abadin 1995) ATSDR categorizes health effects according to the seriousness as serious less serious or minimal A less-serious effect can be defined as changes that will prevent an organ or organ system from functioning in a normal manner but will not necessarily lead to the inability of the whole organism to function normally Serious effects are defined as effects that preshyvent the organism from functioning normally or that can cause death Subtle effects that they may be components in the sequence of events that leads to toxicity are usually categorized as minimal (Pohl and Abadin 1995)

32 A TSDRs gUidance document

The guidance document (ATSDR 2003) provides instructions on classification of some endpoints that may be controversial as to the seriousness of the effects As noted in the guidance document exposure to many substances may result in adaptive changes in the liver that are characterized by induction of the mixed funcshytion oxidase enzyme system and proliferation of smooth endoplasmic reticulum Modifications occurring in the mixed function oxidase system as a consequence of the adaptive response may potentiate or inhibit toxic responses to other exogenous substances Agents that

induce chemical metabolizing enzyme systems (eg aceshytone) generally tend to potentiate hepatic injury proshyduced by compounds such as chloroform carbon tetrachloride or halothane For ATSDR this is an espeshycially important concept to consider because in addition to the specific chemical causing adaptive changes there is the potential for exposure to many other substances at NPL sites (ATSDR 1996b 2003)

The borderline between adaptive physiology and toxicity (functional impairment) is not always well delinshyeated The following guidance provides general direction for assessing hepatic adaptive responses although this guidance is appropriate in most cases there may be exceptions However for the purpose of assessing the biological significance of adaptive responses in the liver the following criteria should be used biochemical changes characterized by induction of enzymes of the mixed function oxidase system along with morphologic changes of hepatocellular hypertrophy and proliferation of smooth endoplasmic reticulum should be considered potentially adverse and should be classified as a less serishyous LOAEL Other supportive changes that may be observed include increased organ weight hepatic enlargement and accentuated cytoplasmic eosinophilia To maximize the accuracy of assessing hepatic (or other) adaptive responses in addition to the guidance given here this interpretative process is accompanied by insightful case-by-case analysis (ATSDR 1996b 2003)

Similarly the whole clinical picture has to be evaluated for effects classified as less serious LOAELs versus serious LOAELs In animal studies normal ranges are often not well established and statistical increase in liver enzymes is frequently classified as a less serious elTect however when the increases are combined with other effects showing a threat to the organism from a serious damage to the liver they would be classified as a serious LOAEL In contrast normal ranges and clinically defined pathological levels are used to identify LOAELs in human studies

Other instructions in the guidance document pertain to a table with examples of hepatic health effects classifishycation (Table I) Some elTects need further evaluation as

Table I Hepatic effect end points

Effect Less Serious serious

Altered liver enzymes + Hepatomegaly (enlargement of the liver) + Porphyria (disturbance of +

porphyrin metabolism) Hepatocyte vacuolization + Congestion ofliver + + Hepatic necrosis + Cirrhosis + Jaundice + Gall bladder effects + + Fatty changes in liver + + Hepatocellular degeneration + +

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to the seriousness based on information provided in the study the effects were described in (ie they can be serishyous or less serious)

33 Hepatobiliary effects and related MRLs

MRLs based on specific hepatic and biliary endpoints are listed in Table 2 Changes in liver weight and hepatoshymegaly are the most commonly used endpoints as crude indicators of hepatotoxicity in animal studies MRLs based on the LOAELs for these endpoints include MRLs for acenaphthene chloroform di-N-octyl phthashylate diethyl phthalate fluoranthene fluorene vinyl chloshyride 11 22-tetrachloroethane and 14-dichlorobenzene MRLs based on the NOAELs for these endpoints include MRLs for hexachlorocyclohexane hexachloroshyethane dieldrin 12-dichloroethane 123-trichloroproshypane and I4-dichlorobenzene Histologically these effects are confirmed as hypertrophy (an increase in size of individual cells without an increase in cell numbers) or hyperplasia (an increase in liver size as a result of an increase in cell numbers) (Evans and Lake 1998) MRLs based on the LOAELs for these endpoints include MRLs for aldrin and 246-trinitro-toluene MRLs based on the NOAELs for these endpoints include MRLs for chlordane HMX and DDT

Clinical chemistry is an important tool for detecting hepatobiliary effects and serum enzymes are the markshyers most often used to detect the injury Increased levels of enzymes such as sorbitol dehydrogenase (SOH) ornishythine carbamoyltransferase (OCT) and alanine transshyaminase (AL T) [previously known as serum glutamic pyruvic transaminase (SGPT)] are typical markers for injury to hepatocytes Other enzymes such as aspartate transaminase (AST) [previously known as serum glushytamic oxaloacetic transaminase (SGOT)] and lactate dehydrogenase (LDH) are also used but they are not specific to hepatic injury and may be increased following injury to other organs (eg kidneys) and muscles MRLs based on the LOAELs for these endpoints include MRLs for chloroform chloromethane xylene 44shymethylene bis(2-chloroaniline) 44-methylene-dianishyline MRLs based on the NOAELs for these endpoints include MRLs for bromoform carbon tetrachloride chloroform and II-dichloroethene Biliary injury is most often detected by elevated levels of enzymes such as alkaline phosphatase (ALP) 5-nucleotidase (5-NT) and y-glutamyl transpeptidase (y-GT) Again ALP is not specific just for the biliary injury and can be increased in other conditions (eg bone disease) MRLs based on the NOAELs for these endpoints include M RLs for carbon tetrachloride endosulfan and 12shydichloroethene Other biochemical changes are indicashytive of changes in the liver function Therefore LOAELs for decreased blood glucose levels (indicative of hepatic necrosis) decreased blood urea nitrogen (BUN) levels

(indicative of liver failure) and increased serum bilirubin (indicative of hepatitis cirrhosis etc) were the bases for MRLs for kerosene methyl-t-butyl ether and 23478shypentachlorodibenzofuran respectively A LOAEL in rats that showed a decreased hepatic uptake metaboshylism and biliary excretion of imipramine (ie hepatic function test) was the basis for an acute oral MRL for toxaphene

Histological examination of hepatic tissue gives the most accurate picture of liver injury Findings are usushyally described with respect to site (ie centrilobular midshyzonal and periportal) extent and cytological changes Many hepatotoxic chemicals induce a whole range of effects depending on the dose On one end of the range are mild effects such as hepatic vacuolization MRLs based on the LOAELs for this endpoint include MRLs for bromoform carbon tetrachloride jp-4 jp-5 jp-8 methylene chloride and 11 22-tetrachloroethane MRLs based on the NOAELs for this endpoint include MRLs for bromoform chloroform and mirex

MRLs based on the LOAELs for fatty degeneration or steatosis include MRLs for chlorodibromomethane hydrazine jp-4 jp-5 jp-8 and 12-dichloroethene An MRL based on a NOAEL for steatosis was derived for carbon tetrachloride Inflammation of the liver was also reported with exposure to some chemicals MRLs based on the LOAELs for hepatitis include MRLs for chloroshyform jp-7 and 12-dimethyl hydrazine An MRL based on the NOAEL for hepatitis was derived for bromoshyform The most severe cell injury results in cell death According to the extent massive necrosis and focal necrosis are recognized Focal necrosis can be repaired by the liver repair mechanism MRLs based on the LOAELs for focal cell necrosis (ie less serious effect) include MRLs for isophorone and 12-dichloropropane An MRLs for mirex was based on the NOAELs for necrosis Another serious effect is liver cirrhosis defined as hepatic fibrosis and nodular regeneration and associshyated with chronic exposure to chemicals such as carbon tetrachloride and ethanol

By definition MRLs are based only on non-cancer effects (Chou et aI 1998) However pre-cancer endshypoints need further evaluation It is recognized that hepatocellular tumors develop from foci of altered hepashytocytes (Evans and Lake 1998) The alteration is expressed phenotypically as foci with increased eosinoshyphilia or basophilia or they may appear vacuolated (high glycogen levels) They may express fetal enzymes such as y-GT or the placental form of GSH S-transfershyase and changes in phase I enzymes (decreases) and phase II enzymes (increases) that are used for metaboshylism of xenobiotics It is not clear if all the foci can develop into tumors if some of them are already small in situ carcinomas or if they need further genetic damage to develop malignancy (Evans and Lake 1998) A NOAEL for dose-related statistical significant liver cellular

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~ 0- 0- 0- ~ 0- ~~

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00 Bi W Wang Y Huang M et aI 1985 Effect of vinyl chloride on tesshy Gaworski cL MacEwen lD Vernot EH et aI 1984 Comparison8 ~ ~ 00 - - 00 2c ~ s U s U s U s U ~ 00 tj0- 0- 0- ii ~ gp ~ - p) u o -o~-o-o-o- - - - tis in rats Ecotoxicol Environ Saf 10281-289 of the subchronic inhalation toxicity of petroleum and oil shale JPshy- ~ u ~ u ~ u ~ 0 - ~ ~gg Cl Cl ~ sect 5 e ~ ~ ~~ ~~ ~~ 0 Cl sect 5l Bornski H Sobolewska A Strakowski A 1967 Toxic damage oflt~

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g E 5 jet fuels In MacFarland HN Holdsworth CE MacGregor ~ o~ Cl 0 0 -lt -lt 01 -0 0 middot6 ~ c-c-c-c--lt(l) 01 01 c 0 01

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o 0 U U cd ~ 0 gt gt 0 1-0 eJJ vc 0 cd _ 0 ~ _ 0 c 8 - 8 ~ v 0 0 S cd cd

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0 - 0- 8 J Condie LW Smallwood cL Laurie RD 1983 Comparative renal paradichlorobenzene Arch Ind Health 14 138-147

gt and hepatotoxicity of halomethanes bromodichloromethane Japan Bioassay Research Center 1998 Subchronic inhalation toxicity 01 gt gt bromoform chloroform dibromochloromethane and methylene and carcinogenicity studies of carbon tetrachloride in F344 rats -0 01 01gt gt gt gt -0gt0lJ gt01gt gt01 01 01 gt ~ gt chloride Drug Chem Toxico 6 563-578 and BDFI mice (Studies Nos 0020 0021 0043 and 0044) Kanagshy

0Iti ~ 01-0 0lJ ~ 01 015 ~ 5 -OOlJ ~ Elovaara E Engstrom K Hayri L et aI 1989 Metabolism of antishy awa Japan Industrial Safety and Health Association Japan Bioasshy~ ~ ti ti ~~8 0lJti0lJ ~ 0lJti ~ 8 ~ ~ 8 ti ti 8 8 8 ti 8 8 pyrine and m-xylene in rats after prolonged pretreatment with say Research Center (Unpublished report to the Ministry ofti8 ti8ti ti ti8 N N

-0 0 ti 8 ti 8 8_ ~ 8 8 8 o 8 8 8 0 88 xylene alone or xylene with ethanol phenobarbital or 3-methylshy Labor) Hirasawa Hadano Kanagawa 257 Japan88 8 -r 8 or) N o o 8 8 0lt 0 or) N 8

N o oO~ oorshy ~ o o o o o cholanthrene Xenobiotica 19 945-960 Khasawinah AM Hardy CJ Clark ac I 989a Comparative inhashy00 -00 o 00 o o o o o o o g d g o gg o EPA 1988 US Environmental Protection Agency l3-week mouse lation toxicity of technical chlordane in rats and monkeys 1 Toxishy

Q) oral subchronic toxicity study with fluoranthene Prepared by Toxshy col Environ Health 28 327-347 Q) - - - - - - - - - icity Research Laboratories LTD Muskegon MI for the Office of Khasawinah AM Grutsch IF I 989b Chlordane thirty-montha a a a asect ~~ Q) u u ~ u Solid Waste Washington DC tumorigenicity and chronic toxicity test in rats Regul Toxicol E sect 2

ltJo _0 middot2

u

a middot2 middot2 middot2 ~Eg u

Q)~ E E E E E o E E EPA 1989c US Environmental Protection Agency Mouse oral subshy Pharmacol 1095-109 dJ =S ~ 2 2 2 s -c c ltJ u c c -c- u u chronic study with acenaphthene Study conducted by Hazelton

Laboratories Inc for the Office of Solid Waste Washington esters and related compounds-and in vitro correlations Environ 5 U 5ltlt 5 Ult 5 o lt 5 5 U 5 U 5 o ( 5u ( Lake BG Gray TJ Gangolli SD 1986 Hepatic effects of phthalateCl

DC Health Perspect 67 283-290 2 2 2 9 2 o 0 EPA 1989d US Environmental Protection Agency Subchronic toxicity Larson JL Sprankle CS Butterworth BE 1994a Lack of chloroshy- - - - - ~ ~ ~

in mice with anthracene Final report Hazelton Laboratories Amershy form-induced DNA repair in vitro and in vivo in hepatocytes of ~ 01 01 ee ] e e Ole~I- - ~~~ sect ] sect sect ] c sect sect ] sect c cc secto ica Inc Prepared for the Office of Solid Waste Washington DC female B6C3FI mice Environ Mol Mutagen 23 (2) 132-136 ~ 00 000 o 00 5 5 o o 5 5 o o o o 5 55 o

EPA 198ge US Environmental Protection Agency Mouse oral subshy Larson JL Wolf DC Butterworth BE 1994b Induced cytotoxicshy chronic toxicity study with Ilurene Prepared by Toxicity Research ity and cell proliferation in the hepatocarcinogenicity of chloroshyLaboratories Ltd Muskegon MI for the Office of Solid Waste form in female B6C3Ft mice comparison of administration by Washington DC gavage in corn oil vs ad libitum in drinking water Fundam Appl

EPA 1994 US Environmental Protection Agency Methods for derishy Toxicol 2290-102

vation of inhalation reference concentrations and application of Laug E Nelson A Fitzhugh 0 et aI 1950 Liver cell alternation sect 01 inhalation dosimetry Office of Research and Development Washshy and DDT storage in the fat of the rat induced by dietary levels of Is s

-0 -0 -0 -0 middotc middotc middotc ington DC EPA6008-901066F to 50 ppm DDT 1 Pharmacol Exp Ther 98 268E o o o o 8 g a a 6 Evans JG Lake BG 1998 The digestive system II the hepatobiliary Levine BS Rust 1H Barkley U et aI 1990 Six month oral toxicity o 2 ltt u u 8 j j ~ 1 ~ 2 system In Turton l Hooson J (Eds) Target Organ Pathology study of trinitrotoluene in beagle dogs Toxicology 63 (2) 233-244

Q)c ~ =5 E E 8~- D E E E Eu 0-0 ~ ~ ~ ~ Q) Taylor and Francis Bristol PA Masuda Y Yasoshima M Nakayama N 1986 Early selective and E ~ae2 E 01 01 01 D a E t2~ E o 5 sect o o 8 5 8 o o 0 o Fitzhugh OG Nelson AA Frawley JP 1950 The chronic toxicishy reversible suppression of cytochrome P-450-dependent monoxygenshy01 ~ o o 8 2 2 t c middotc ] E E 8 8D D o o o o o o o o 0 oD u _ o of of of ties of technical benzene hexachloride and its cr ~ and y isomers l ase of liver microsomes following the administration of low doses of-0 - 0 0 2 01 01 01 01 01 a a a a a a aa a ltlt ltP)P) P) P)U U U U U ea U U U U U U uu U Pharmacol Exp Ther 100 59-66 carbon disulfide in mice Biochem Pharmacol 35 3941-3947

168 H R PoM c-H Sl Cholll Reglliatory Toxicology and Pharmacology 42 (2005) 161-171 H R PoM C -H Sl Cholll Reglliatory Toxicology and Pharmacology 42 (2005) 161-171 165

for acenaphthene ftuoranthene and 112-trichloroethshy ATSDR has joined the search for alternative methodshyane These MRLs correspond with the respective RIDs ologies to refine the chemical health risk assessment ~ when adjusted for duration of exposure (ie divided by New approaches to risk assessment eg benchmark ~ E CD-g 00- 00rshy10) MRLs for carbon tetrachloride chlorobenzene dose calculations physiologically based pharmacokishy r-

0gt CD 0gt 0gt ltl0 c 00 ~ -0 N 2 ~oo0gt 00styrene 14-dichlrobenzene and PBDEs differ very netic (PBPK) modeling and quantitative structure-activshy r- r- o a gt 0 ~~ ]V) 0gt ~ ~~ 000gt- ~ -0 0 ~ _ _~ N ~ ~ r- shy 0 ~~ ~ 00 S0gtslightly The differences are due to the studies andor ity relationships (QSARs) are being explored Better CD 0gt _r shy

2V) 00 0gt 0gt CD a 0 ~ ~ middotS ~ - ~ _=a0l

~

00 0gt 0gt 0gt 0 ~ 00endpoints and uncertainty factors used for the derivashy understanding of toxicokinetics and toxicodynamics of - - V) c - -shy~ ~2~~gta-_ -=-shyS QJ--

0gt 0 0gt ~- c- - ~

~ - 00 ro-= c 00 0gt ~ 7 ~ - 0 ~ c t) ~000tion The only noteworthy difference was between the environmental chemicals and their interactions with the o 00gt 0gt c - - ) ooooc

Of) ~ nJ ~ ~ -

~ 01gt- gt ~ ~ ~u ~ ~~ ~ ~t)J2t)000 gt l ) ) c ~~ l c _0 0 Olt C c~ = ~ t C )chronic oral MRL of 2 x 10-5 mgkgday for vinyl living organisms on molecular levels will enable the f- c 01gt OJ lt u gt lt 0 ~

o o lt 0chloride and a corresponding RID of 3 x 10-3 mgkg ~ ~= sect N l lt o c

0 8

c laquo~

c c middotS o

sect~~~~~EsectMoof-_ _ _ ~ fshy gtt

c c iU

cl

health assessors a better evaluation of the health risks XXU ~j j ~lt d ~ ~ X UJUJu o X2ltOltviOX2-2 f--~ U day The RID for vinyl chloride is based on liver cell This understanding will also improve the risk assessment polymorphism in rats reported in the Til et al (1983 of joint toxic action of environmental chemicals in mixshy fJ - ~

_ VO - - ~~ ~ rn c ~ ~ ~ ~ ~= ~ ~ shy1991) studies EPA used a PBPK model to calculate a tures and in combinations with pharmaceuticals viral tU~ 0 0 gt_ oS c tU tU (l) 0 ~ blj ~ tU o ~ ~ 2 ~ r ~ 0 ~ ~E ~ ~ t ~ ~ ~ ~~ 0_rhuman equivalent NOAEL of 009 mgkgday An UF agents and other hepatotoxicants 0 - tU gt c- - - ~ ~ OJ c ~ (l) 0 E Crn (l)

1-0 0 ~c ~ = ~ u 6 S ~ 0 Vi ~ 3 c ~ -5 ~ ~ ~ 1-0 ~ ~ ~ -= ooo_~ ~jcl01)-= 0 ~oO OJ gt - ~rn~ dJl-oSof 30 was applied 3 for animal to human extrapolation 00 ~ ua e (l) ~ flJ 3 ua ~ 0 0 C rn 0 c ~ _ ~ fI (l) 0 c ~ 2- ~ 0 - _ u c a ~ coc _ (l) ~ 1-0 OJ 0 r ~ E a(l) (l)Oand 10 for human variability A LOAEL of 0018 mgt ~ ~ ~ 5 sect ~ ~ ~ ~ ~ ~ ~ ~~ 0 ~ ~ ~ 0 ~ sect ~~ ~ ~ ~ sect g ~ ~ ~ ] Eo ~ g-References - 5 E gt IV ~ ~ c a ~ tU j j ~O Q) - 1-0 ~ ~ _ gt- _c 0 3 0S rn rnkgday for basophilic foci in rats in the Til et al (1983 r- r-c 0 ~ ~ ~ ~ ~ b g ~ 0 g ~ a ~ ~ b t u 2 ~ ~ ~ ~ -5 ~ ~ E B g c 2 ~~f- ~a01gt~-~oc~U cc~ ~ gtgtE02 _ 01991) studies was used to derive a chronic oral MRL o 0 l - 0 ~ - Ic 0 ~ c 0 ~ = OJ ~-~ ~ Cl) E 0 ~ c en j gt- 0(l) Q)Abadin HG Murray HE Wheeler JS 1998 The use ofhematologshyrIJ rIJ -lt e ~ sect c g E C v ~ B c ~ Q) ~ amp ~ 2 ~ sect ~ ~ ~ B ~ ~ ~ c ~ ~ ~middotumiddot~ ~ b ~ ~for vinyl chloride A UF of 1000 was applied 10 for use ical effects in the development of Minimal Risk Levels Regul Toxshy ] 13 13 ~ ~ ~ ~ ~ 0 sect 2 ~ ~ ~ ~ ~] 2 2 ] ~ ~ ~ ] ~ ~~ ~ ~ 5 2 ~ ~ ~ ~ ~ -g ~ sect ~

of a LOAEL 10 for animal to human extrapolation icol Pharmacol 28 61-66 a3 ~ ~ ~ ~ 2 0 ~ ~ E~g ~ ~ ~ 5 ~ ~ ~ ~ ~2 ~ ~ ~ t d 0 0 g ~ ~ g ~ g ~ ~ c ~ ~ and 10 for human variability As mentioned previously Adams EM Spencer HC Rowe VK et aI 1952 Vapor toxicity of t t t 0 ~ 0 ~ S E ~ 3 ~ E E t 2 a ~ t t t ~ c ~ f B -g t e e S ~ ~ j 0 8 0 ~ ~ t c

C c 0 2 -g e- E rn ~ 0 ~ gt ~ t t c c c oa ~ ~ g gt E ~ ~ ~ fr ~ ~ ~ ~ gt ~] OJ~Cl)

carbon tetrachloride determined by experiments on laboratory anishy 0 - - 1-0 (l) ~ c ~ ~ _ ~ 0 _ 0 U o~ - - 0 u ~~ g 0 r 0 0 gt loc u 0 0 ca recent re-evaluation of the chronic oral MRL for ~ bh ~ ] 15 n) 15 0 g- M ~ M2 53 1sect ~ 15 ~ ~ ~ ~ Jsect ~ isectsect 15 8 ~ 8 8 15 Jsect M 15 ~ Jsect 15 ~ lsect 15 -g Jsect ~ mals Arch Ind Hyg Occup Med 6 50-66 vinyl chloride concluded that liver basophilic foci are 0 ~ E 2 ~ ] ~ ~ gt ~ -= ~ ~ c e ~ tO EE ~ 5b ~ ~ ~ fr E middots oSS i i r ~ ~ ~ ~ ~ E E ~ ro i ~Air Force 1991 Tumorigenic evaluation of jet fuels JP-TS and JP-7

fI

generally considered preneoplastic and that it would 5 5 5 ~5 c 0 u ~ 5 t5 ~ =5 5 f 5 ~5 5 5 ~ 5 5 ~ 5 ~ 5 5 5 5 5 5 5 5 5 55 ~ 5 oS 5 ~ 5 ~ Report No AAMRL-TR-91-0020 Wright-Patterson Air Force ~~~~~~~~~~~0~~~~~~_~~O~-~~~~~~~~~~~~~~~~=

UJUJUJ~UJUJ~~UJuUJ~5UJ~UJ~UJ UJUJUJ~UJUJ UJ~UJUJUJUJUJUJUJUJUJUJw~UJUJUJ~UJ~be more appropriate to base the vinyl chloride chronic Base OH Aerospace Medical Research Laboratory Aerospace laquoltclt ltuoltglt~ltcltltlaquoltclaquolt]laquolaquolaquolaquolaquolt~laquoltlt~oral MRL on the NOAEL for liver cell polymorphism Medical Division Air Force Systems Command OOOO~O~OOmiddottOoto~OOOOO~O~OOOOOOOOOOOO1gtOOO)Omiddot-

2 ~ ~ -5 2 2 15 ~ ~ 2 ~ amp 2 -5 ~ ~ 2 E ~ ~ 2 ~ ~ 2 E 2 ~ ~ ~ ~ ~ ~ ~ ~ 2 2 2 E 2 ~ ~ E 2 ~ Air Force 1984 Ninety-day continuous inhalation exposure to petroshywhich is considered non-preneoplastic The proposed

leum JP-4 jet fuel In Toxic hazards research unit annual technicalrevised chronic oral MRL for vinyl chloride is 000 o o o o o o 000 00 o 00000000000 000 000 o 8 o o o o 000 00 o oOOOOOOOMOOreport 1984 Report No AMRL-TR-84-001 Wright-Patterson Air OM 8 M M M M M - MO(f)MMOM 288 8

M3 x 10-3 mgkgday (ATSDR 2004) This MRL is curshy Force Base OH Aerospace Medical Research Laboratory Aeroshyrently released for public comments in the draft toxicoshy space Medical Division Air Force Systems Command Document

logical profile No AD-AI4785717 pp 46-62 gt gt gt gt gt gt gt gt gtgt gt gt gt ~ SArmy 1985 HMX 13 week toxicity study in rats by dietary adminisshy gt gt ~ ~ lt gt gt ~ gt 0

tration Ft Detrick MD US Army Medical Research and Develshy -5~ ~ lt gt Ob gt ~ == S~ lt gt ~ ~ ~-5]gt ObOb ~

Oblt lt Ob ~ E ~~~ Ob lt E ~ ~ ~i ~ Ob Ob ~~~ opment Command US Army Medical Bioengineering Research ~ ~ ltObE Ob E ~ V) ~ E E~ Ob clt~~ EObltEE~E E4 Conclusion ObEc V) ~ lt ~~E -0lt cObE EObEObccEoo E~Eand Development Laboratory (authored by Everett et al) E _ c E 8 N E

V) 8 ~ E o Ob o E E ~ OOb g EObObE_ E cc-o8 ampE~ o ATSDR 1992 Public health assessment guidance manual US - 0 N q q E o E o 0 8 E o ONEEMOMMMOO ON 0 q o 0- o000 o o M o -0 o 000 o OOOgtMOOOOOOO 000

As demonstrated here the hepatobiliary endpoints Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry Atlanta GAare important in the derivation of MRLs Hepatoxicity OJ OJ OJ (l) tU (1) (l) OJ OJu uNTIS PB92-147164 j j ~ ~~ ~~~

is seen with many chemicals and for some the liver is a a a a a a a aATSDR 1996a Minimal risk levels for priority substances and guidshy OJ u u ~ ~ S ~ OJ primary target of their toxicity Proper classification of ]~ ] u c c E E c ] ~ ] ] ~ ] ] ] ~ ~ ~

OJ sect 0) 0 sect sect sect sect 0 E sect sectance for derivation Federal Register 61 (101)25873-25882 u u

OJ o

2 -

l ~ 2 ~ ~ 2 ~ t ~ e 2 2 S 5 (l)

effects is crucial for the process of MRL derivation ATSDR 1996b Guidance for developing toxicological profiles -c - sect C C c sect c -c ltU c _U __ U ___ UUU U - U c --c CCCCCCCCCCCU lt U U u ltlt This requires clear understanding of pathology and Agency for Toxic Substances and Disease Registry US Departshy

ment of Health and Human Services Atlanta GApathophysiology Consistency in classification of c c c c c c c c ATSDR 2003 Guidance for developing toxicological protiles 2 2 2 2 22 22

similar endpoints across the different studies and - ~ ~~~J ~~ (update) Agency for Toxic Substances and Disease Registry US chemicals has great significance in MRL derivation -0] sect ~ ~ ~ ~ ~ sect sect~~ ~sect sect ]e]]]]~]]]~ sectsectsect sectDepartment of Health and Human Services Atlanta GA 00 o o o o o o o 000 00 o 0000 000 oThat is why ATSDR has a guidance document to help ATSDR 1995 Toxicological profile for diethyl phthalate US Departshy

with the classification and a workgroup of scientists ment of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry Atlanta GAdiscussing the proper classification of health effects on Available from wwwatsdrcdcgov a case-by-case basis In reviewing the past decisions

ATSDR 1996c Toxicological profile for carbon disulfide US ~ shy ~regarding classification of hepatic effects this article Department of Health and Human Services Public Health Service oJ oJ sectx

strives to bring this issue in focus ATSDR uses up-toshy Agency for Toxic Substances and Disease Registry Atlanta GA ~ OJ 0 ~cX

c c

date methodology for the MRL derivation where Available from wwwatsdrcdcgov j ~ c oU () () c ~ c cOj i o o c c (1)

2~ nJ C 1 tbiomedical judgment plays an important role (eg ATSDR 1999 Toxicological profile for chlorophenols US Departshy c c c c -Uc c _ 0 0 0 cc ) sect ~ gtshy 0 u u ) ~- - shyment of Health and Human Services Public Health Service U _ccc ~ application of UFs) It is helpful to realize that E c c c c 0) I U U U (1)c 11) flJAgency for Toxic Substances and Disease Registry Atlanta GA sect sect ~ ~~ E 5 2 2 2 2 (1) 0 Q) a c~ ~ c ltZ -= o 0 o o cATSDRs results are comparable with other agencies lt2lt2E u u c tU2 5 2 1 ~ + ~ e ~ Available from wwwatsdrcdcgov 000 ~ ~ ~ o 0 t ~ 3 c Cc 22 2 o c c 0 u U U U ~ ~ = ~ gtlt c c co ~ ~that derive health based guidance values for hazardous ATSDR 2004 Toxicological profile for vinyl chloride Update Draft 000 _-f-bull

~ ~ ~ ~ u

00 0 o~nr- 2-=-=-=-= ~ ~ Q) ro 222 ~~o c uchemicals for Public Comment US Department of Health and Human Ser- c ~ 0 0 uuu U Cl i5 i5 i5 i5 UJ GGx xx X poundg~~~~~~~~~ -f- ~

166 HR PoM C-HSf Chou I Regulatory Toxicology and Pharmacology 42 (2005) 161-171 H R PoM C-HSf Chou I Regulatory Toxicology and Pharmacology 42 (2005) 161-171 167

~ changes (hepatic foci areas of cellular alterations) in rats ethane 14-dichlorobenzene and 44-methylene-dianishyJ e

13 was used to derive a chronic oral MRL for methylene line For respective endpoints that were considered as ltIJ - ltIJ chloride A LOAEL for basophilic foci in rats was used minimal see descriptions in Table 2 A default UF ofco co ~

on onr- ~ 00

~ ~ ~ s to derive a chronic oral MRL for vinyl chloride A recent 10 was used for most of the animal to human extraposhysect~ ~ ~ ~

=-~ r- 5 r- r- J ~ shy re-evaluation of the chronic oral MRL for vinyl chloride lation of study results An UF of 3 was used for inhalashy~oo ~ t shy Of) ~ o r-o- t shy 0 t- ~ 6~~ ~ 0 00 $ ltT 00 ~ 5 -shyM-- co 00 ~ ~ -ltIJ t) ~ ~o r-~ ~ ~E= concluded that liver basophilic foci are generally considshy tion exposure route in cases of MRLs derived for ~~ 0- ~ ~ - co t-

Q) ~ ~

~ J 0- J ~ - 0 0 ~ ~

UI~~- ~~ ea~el J t t ~ -~ ~ 0lt ered preneoplastic and that it would be more approprishy carbon tetrachloride chloroform hydrazine JP-4 JP-t ~

~ ~~- J M o J(1) _ - cu JJ J 11i ~ - 00 ltIJ 00 J ~ ~ l ~sect J J-shy - - ~ ate to base the vinyl chloride chronic oral MRL on the 5 JP-7 JP-8 methylene chloride 1I-dimethylhydrashyu ----~ ~shy ltIJltIJ -~ ~~tl gtltIJ ~ ca ca ~ --ltIJ - t --0 0 on

~

-ltIJ C-tI-V o~ -o-0 gt~ ~~ - C ~ sect ~ ~ sect raquo ~ sect NOAEL for liver cell polymorphism which is considshy zine and 12-dichloroethane The change was mostly~ 0 0 gt 0 l l ltlJo == ~ r gj= 0 ~ -0ltIJ f- ltIJ E ~ o -2 ~ 2 ~ OJ 0 of- l ~ iJ 3 l ~ ~ ered non-preneoplastic In contrast ATSDR did not justified by calculating the NOAEL human equivashy~ ~ f- -l 0 6c ~ f- OzU u ~ ~ c ~ CZ5-Io V5 ~ 5 ltIJ

~ derive an oral chronic MRL for decabromodiphenyl lency concentration (HEC) (EPA 1994) Similarly an o tIlt-~ 0 ~ ~ ~

-0 - ether based on a LOAEL for thrombosis because the UF of 3 for interspecies extrapolation was used for OJ E~ sect S ~ ~ ~ ~ tJ _

es sectC ell __ 0 0 0 ~ OJ) c Il -oJ LOAEL for thrombosis was also associated with preshy acute inhalation exposure scenarios in case of chloroshy] =5 ] ~ ~ E ~ ~ t Et) ~ ~

c ~ OJ)S C ~ ~ bO ~ c l) 0 bl)c 0I t J neoplastic nodules in the liver form because dosimetry adjustment was made and anj 0 C ]a ~ ~ 0 (1) [i I-o~ 0 C - Ci] o ~g E a 8 ~ ~ ~ ] ~ ~ ~ ~ 3 = d 5 g~ E ~ ] 0 ltIJ UF of 3 was used to account for toxicodynamic differshy

~ Eo-52 0 0 rot () 0 0 t c ~ 0 0 t ~ s ~ ~ o _uf- 00 - - -0 -0 gtltIJ 2 2 _~l l -0 f- ~ o

34 Use ofuncertainty factors encesc J 0 = 0 0 0 c g gt- rn ~ rn = en OJ) OJ) eo ~ ~ = laquo1) D u 0 JCIl bIj sect~a laquo CIl 0 bO a ~ 0 ==~ = (I) 19 0 ~ 0 - (I)] c ~ ~ lt1-0 0 In some instances modifying factors (MFs) are usedI ~~Oj ~~ sect~ E ~ ~ ~H~H~ o~ ~~ ~~~ ~ ] -l ~ tI E tI ~ c s s II) h I1J S Q tI 1-0 0 s 1-0 1-0 E c ~ u sect ~ lt OJ Uncertainty factors (UFs) are used in the process of to account for additional uncertainty associated with the(I) ~ ~ U - - tt tt - til I1J - I1J ~ 2 = _ V c(I) (I) 1-0 (I)

01 D -a ~ ~ a ~ ~ ~ ~ 0 ~ ~ ~ ~ ~ ~ ~ amp 5 ~ ~ go ~ CIl ~Q 0 Z ~ MRL derivation to account for uncertainties associated guidance value For example an MF of 3 was applied 5 tj ~ 0 0 I1J ~ fJJ ~ l ~ l 2 Q b 0 ~ (g 0 ~ 0 ~ ~ ~ ~ 0 ~

~ ~ amp 0 = Il) ~ amp frVj S ~ pound ~ ~ 0 ~ ~ ~ 0 ~ amp u ~ gt u sect- fJJ ~ 0 - ~ with extrapolation from a LOAEL to a NOAEL and for insufficient diagnostic data to determine the seriousshygt raquo~~~ ~a ~~ ~ ~ 2 -g -g~poundtjgjroo~~ ~B5 580 ~ 5 ~ 1-0 5 gt 8 ~ ~ 1-0 1-0 U c ro c ~ u CI 1-0 Il) lc 1-0 1-0 a 1-0 0 ro ~ u 1-0 I1J tI ~ 0 from animal to human data and with adjustments for ness of hepatotoxic effects in a study in exposed workers

~ ~

- -~ - ~ 0 c 0 en 0 ~ ~ 0 ~ c ~ ~ rn rn -o - 9 rn ttJo C en - ~ en ~ g g ~ s ~ E 0 g c 5 ~ ~ ~ ~ ~ 5 ~ E 5 ~ -sect ~ 5 g ~ g (I) U c2 ~ 5 g ~ sect

middotE sect intraspecies variability UFs with default values of 10 are (Phoon et ai 1983) used for deriving the intermediatetltIfJJ u tlu U tImiddot utl)fJJul=Ou tI) _ fJJtI)tI)l-obO ro bO tI) ~ l ~ ~ - E ~ ~ ~ ~ ~ E ~ ~ II) CI ~ ro I1J 0 ro ro 0 tIJ CI ca~ usually used for all three categories of extrapolation inhalation MRL for chloroform Similarly an insuffishy~ e ~ 0iJ (I) ~ E ~ ~ N 1-0 E ~Q e Q ~ E c C e ~ E ~ middotc E a 1-00 0 E-c C c c tI) ~ c s C C = c C cu C uc ~ C c = c 9 s s c c - c 5 0 ~ ~ c 5 M1-0C __- - 5 0-- ~ - - 0 -_- - - 0 - 0 - - _- - bO_ s - fJJ - 0 5 E However in some cases the uncertainty is decreased cient database was the reason a MF of 3 was used for the

- 111 I -0 I I -01 I 8 I I I OJ I OJl ltIJ I I -5 I EI 111 5 I I 0 II gt1 -0 E 2o -l-l-l on-lJ UJ-l OJ-l -l OJ-l-lUJ o-l fr-l -l-l -l ltlJUJ -l-l-l -l-lJ -l E--l E-l ltIJ resulting in utilization of a lower UF (Pohl and Abadin derivation of a chronic inhalation MRL for 12-dichloshy0laquoltOjlt~ltIJlaquo~ltltIJltgtltltlt]ltJlt~ltltElt5lt~ltltltEltltgltIJltltOjltltIJ I ] 000sect0]~00~0~0]00000~0020~0~000200=~0~00~ 1995) Following are examples of the application of UFs roethane-l 111 -0 Z 0E I I on Z -0 I OJ Z I I -5 I -5 Z S I Z ~ Z Z -0 I I I ~ I Z E -0 I lt I - Z E ~ t 0 other than 10 in the derivation of MRLs based on -en

o 000 o 000 o o gt-0 hepatic effects 35 Comparison with other guidance values0u18 8 8 8 88 8 o ~ 0 8 88 8 8 000 88 o 8 o ~ J 00 OM 00 8 0_ MOO 0- o M M -u OJ Just a few MRLs were based on the endpoints conshy ~o sidered the borderline between adaptive physiology0 ~ Other agencies also derive health-based guidance valshy

ltIJ ~ raquo raquo raquo ~ sect and toxicity (see the section on ATSDRs guidance ues For example the US Environmental Protection-0 raquo OJ OJ OJ raquoraquo raquo -0 raquo raquo-0 -0 raquo OJ raquo ~ ~bbraquo -0 OJ OJ raquo bbOj gtgtOJbb bbOj raquo OJ -0 document) An oral acute MRL for carbon disulfide Agency (EPA) derives reference concentrations (RfCs)OJ OJ OJ bD ~ l Ob-o ~ g~~E ~ ~~ ~~ ~ 6sect was based on a LOAEL in rats (ATSDR I996c) Doseshy for chronic duration inhalation exposures and referenceJEEbb ~o ~ bb~l ~ ~ gt 0 N ~ E- ~ E~E E E~ E E E~ ~ ~ ~

I 08bb ~ ~ 0 E sect oEo 0 ~ gg E sect 0 ~E8 g E E ~ E dependent decreases in hepatic microsomal drugshy doses (RIDs) for chronic duration oral exposures Curshy~ ~ ~ 0 E N 00 ltT 0 0 ~ 0 0 E 0 0 Et-8 0- o E 00 0 OJo 00 o ltT ON N N 00 N ltTOO 00 N o o 0 metabolizing enzymes were detected Similarly an rent RfCs and RIDs are posted on the EPAs web siteE ~~~ o 00 o o 000 o o 00 o o 000 00 ~ o o ~ ~ ltIJ bull intermediate-duration oral MRL for diethyl phthalate (wwwepagoviris) In July 2004 69 RfCs were posted ltIJ ltIJ ltIJ ltIJ ltIJ ltIJ 9~ was based on a LOAEL in rats that showed peroxishy including 8 based on hepatic endpoints From the 358E E iii iii iii iii iii iii ~ ~ iii ~~~ iii iii bull ltIJ OJ I somal proliferation slightly elevated liver weight and RIDs posted 94 were based on hepatic endpoints Many a ua altIJ a altIJ u u a ~ ~~ a u aaa a u

~ ~ ltIJ ltIJ -l 1l ltIJ ltIJ 22 ltIJ 2~ sectsect sect 00- sect 2 ltIJ sect o lt shy

E enzyme activities (ATSDR 1995) The LOAELs were of the chemicals with RfCsRIDs derived from hepaticE sect E E E E EE E o E E E E~ o (I) 1-0 OJ ltIJ ltIJ ltIJ l ltIJ ltIJ ltIJ l s c J- JJu ltIJ J ltIJ ltIJ 2 U I il - u c considered minimal and an UF of 3 was used for effects were not evaluated by ATSDR as ATSDR evalushyo 5 U 5 5 u5 5 5 UUlt 5 5 ]] 5 U ]]] 5lt U lt OJltIJ

on- LOAEL to NOAEL extrapolation in the derivation of ates only chemicals on its priority list (Roney et ai e ~ both MRLs In contrast the acute oral MRL for 4- 1998) In fact only four chemicals had both the RfC and2 2 2 2 2 2 2 2 ~~ iii iii ~ ~ iii iii iii OJ 0 chlorophenol was based on a NOAEL for hepatic the inhalation MRL These included chlordane with aJ ee J J-OJ J J OJ ltIJ shy~I~

o

OJl -- secto c ~ ~ J J J gg J e ee J J ~ee ee sect sect sect l gtlt effects in rats (ATSDR 1999) At the LOAEL level chronic MRL of 2 x 10-5 mgm3 and an RfC of ~ 5 00 5 05 o 5 _0_ 5 o 00 5 5 000 00 o o o -0 0 o ~ foamy cytoplasm clustering of mitochondria and 7 x 1O-4 mgm3

vinyl chloride with an intermediateshy9 E s 0 OJ endoplasmic reticulum were reported These electron duration MRL of 3 x 10-2ppm (8 x 10-2mgm3) and an

E ~

lt2 sect zshy microscopic changes could be considered borderlineJ on RfC of I x 10-1mgm3 II-dichloroethene with an intershy26 ~ E however further evaluation that considered progresshy mediate-duration MRL of 2 x 10-2 ppm (8 x 1O-2mgN ~ 0 2 ltIJ 3

OJ sion of changes with increasing dose in the database m ) and an RfC of 2 x 10- 1 mgm3 and 14-dichlorobenshy e

o ltIJ S f-OJ ~ ~ ~ sect sect~ -5 S sect -g ~ EO caused the endpoints to be classified as LOAEL rather zene with a chronic MRL of I x 10-1ppm (6 x 10-1mg - oJ oJ g ltIJ ltIJ g 2ltIJ E sect ~ 0 0 ~ 2 ~O 32 OJ 0 g OJ OJ en than NOAEL Other MRLs based on minimal LOAshy m ) and an RfC of 8 x 10- 1 mgm3 ltIJ -0 -5 o sect ~ 5 ltIJ ltIJ -0 - ~ raquo c-= -5 raquo0 ~ ~ ~ 0 -5 0- E ltIJltJ a -5-5 ltIJ ltIJ lt 0 ltIJ Il) C cd ltIJ ~ ~ -OJ

bull

ELs that warranted the use of UFs of 3 include MRLs For oral exposure only 14 chemicals had both theS ltIJ - 1 - 0 ~ 0 0_ g -0 -0 o-raquo o 000 o OJ_ ltIJ ltIJ ltIJ ltIJ ~ ~sect sect o J_ 2 2 gt9 ~

gt gt - for bromodichloromethane carbon tetrachloride chloshy RID and the MRL derived Chronic duration MRLsJJ gto 000 o o o o o 0 ~ J ~ 8 --I - u - middots_ 0 OJ JJ a aaa a a a a raquo -5 -5 _ u U ltIJ u a E ~ ~ u u u u u

E - u u Q) ltIJltIJ -OJ OJ rodibromomethane chloromethane di-N-octyl phthashy were equal in value to RIDs in the case of aldrin chloshyN OJ -- ~ is E- N - f- ]~~ E-9 raquo raquo ltIJ iSiS is is is OrA is is o ltT J ~ ~ ~$ - -7 t lti

~ c ~ late ~-hexachlorocyclohexane methyl-t-butyl ether roform DDT and dieldrin ATSDR did not deriveOJ I ~l - r1r1~ N No t V I M ltTU ~ ~ ~f- raquoXen - N N N~ ltT ltT ltT lt E methylene chloride vinyl chloride 1122-tetra-chloro- chronic MRLs but has intermediate duration MRLs