Umt*0SwtM Environment*! Protection . A«*ncv , November 1984 Research and Development METHODOLOGY AND GUIDELINES FOR RANKING CHEMICALS BASED ON CHRONIC TOXICITY DATA Prepared for OFFICE OF EMERGENCY AND REMEDIAL RESPONSE Prepared by Environmental Criteria and Assessment Office Cincinnati OH 45268 ------- DISCLAIMER Mention of trade names or c owner da 1 products does not constitute endorsement or recommendation for use. ------- TABLE OF CONTENTS Page 1. INTRODUCTION ..................... ' 2. CHRONIC TOXICITY RANKIN6 SYSTE* ................. 3. APPLICATION OF THE KETHODOlOGY .................. 4. S0« CONCEPTUAL CONSIDERATIONS. ....••• .......... 5. MODIFICATION AND APPLICATIONS .................. • «•*** 6. REFERENCES ...................... 111 ------- LIST OF ABBREVIATIONS ADI Acceptable dally Intake CERCLA Comprehensive Environmental Response, Compensation and Liability Act of 1980- CS Composite score CWA Clean Hater Act FEL Frank effect level ICRP International Commission on Radlologlc Protection LDso Dose fatal to 50* of test ail"*1? LOAEL Lowest-observed-adverse-effect level MED Minimum effective dose NOAEL No-observed-adverse-effect level NOEL No-observed-effect level OERR Office of Emergency and Remedial Response OSWER Office of Solid Haste and Emergency Response RQ Reportable quantity RVj Dose rating value RVe Effect rating value 1v ------- PREFACE During the past three years the Environmental Criteria and Assessment Office. Cincinnati (ECAO-C1n) of the U.S. EPA has developed a method to rank chemicals based on chronic toxldty data. This ranking system reflects two primary attributes of every chemical: the minimum effective dose and the type of effect elicited at that dose. Although based on observed toxldty data, H 1s not considered to be a health risk assessment. The purpose for developing this chronic toxldty ranking system was to provide the U.S. EPA with the technical background required to adjust the RQs of hazardous substances designated 1n Section 101(14) of the Comprehen- sive Environmental Response, Compensation and Liability Act of 1980 (CERCLA or "Superfund"). This ranking system has undergone a limited peer review and a public review. It may'have applications to other areas of Interest to the U.S. EPA and other regulatory agencies where ranking of chemicals based on chronic toxldty Is desired. ------- 1. INTRODUCTION The purpose for developing this chronic toxldty ranking system was to provide the U.S. EPA with the technical background required to adjust the RQs of hazardous substances deslgnaled In Section 101(14) of the Comprehen- sive Environmental Response, Compensation and Liability Act of 1980 (CERCLA, or "Superfund"). Section 103 of CERCLA requires Immediate notification from any person 1n charge of a vessel or an offshore or an onshore facility who releases an amount of a hazardous substance equal to or greater than Us RQ. Under Section 102(b), the RQ of any hazardous substance defined 1n Section 101(14) of CERCLA 1s 1 pound unless a different RQ has been established pur- suant to Section 311(b) of the Federal Hater Pollution Control Act. This 1s the statutory RQ for each hazardous substance unless and until the Admin- istrator of the U.S. EPA promulgates regulations establishing that quantity of any hazardous substance the release of which shall be reported pursuant to Section 103 of CERCLA. CERCLA also permits the U.S. EPA to establish a single RQ for each hazardous substance regardless of the environmental medium Into which the substance 1s released. The strategy of the Office of Emergency and Remedial Response (OERR) of OSUER 1s to adjust the Section 101(14) statutory RQs using six primary criteria (1gn1tab1l1ty, reactivity, cardnogenldty, aquatic toxldty, acute mammalian toxldty (oral, dermal. Inhalation) and chronic toxldty) and three other factors (blodegradatlon, hydrolysis and photolysis). (Chronic toxldty, for the purposes of this report, 1s defined as toxldty due to repeated or continuous exposure from a single release or multiple releases of a designated hazardous substance.) For each criterion, a five- tiered rating scale Is set up corresponding with RQ values of 1, 10. 100, 1000 and 5000 pounds (X. A. B. C, 0). Since this f1ve-t1ered system was 0721B -1- 03/11/85 ------- successfully used 1n the CUA and the regulated community 1s familiar with H, CERCLA uses this methodology. Unlike the CUA. CERCLA addresses all media, not only water. Therefore, while the strategy selected to adjust the RQs of the designated hazardous sJbstances pursuant to Section 101(14) of CERCLA was based on the precedence established 1n assigning RQs pursuant to the CUA, Instead of using aquatic toxldty as the sole criterion for estpb- « Ushlng RQs, health and welfare effects for other media were also used to adjust the RQs. Each hazardous substance 1s evaluated according to the pri- mary criteria and an RQ value Is determined for each applicable criterion. The "primary criteria" RQ for each hazardous substance 1s the lowest value of all the applicable criteria. , 03/11/85 0721B •*' ------- 2. CHRONIC TOXICITY RANKING SYSTEM The chronic toxUUy ranking system reflects two primary attributes of each chemical: 1. The MED levels for a given" effect following chronic exposures (mg/day for 70 kg man) by alternative environmental media (air. water). 2. Type of effect at the HED (e.g., liver necrosis, teratogenl- dty. etc.). The dose rating for a given chemical 1s based upon the HEO transformed to values ranging from 1-10 using the graph given 1n Figure 2-1. Substances having an effect at a low dose (I.e., those that are more highly toxic) will be given a high rating on this graph, while those requiring a high dose (less toxic) will be given a low rating. Similarly, the rating for the observed effect at a given dose for a given chemical will range from 1-10 depending on severity using Table 2-1. with 10 being the most severe. These values must be assigned on a chemlcal-by-chemlca1 basis. A final composite score (CS) 1s determined by multiplying the dose rat- Ing by the effect rating. The possible range of CSs Is thus 1-100. Using this scheme, only those compounds eliciting what are judged to be the most severe effects at low levels of exposure would be assigned high CSs; com- pounds that elicit minimal effects at high doses would be assigned low CSs. The following text gives step-by-step details for this procedure: s 1. Identify subchronlc or chronic NOAELs, LOAELs or FELs* based on animal or human data from the available literature. Note the dose/exposure and the effect. 2. Convert all NOAELs, LOAELs and FELs to units of mg/kg/day. Inhalation, dietary or drinking water exposure data will be converted to units of mg/kg/day doses based on the methods outlined previously (U.S. EPA. 1980). 3. If the NOAEL, LOAEL or FEL 1s based on subchronlc exposure, a corresponding chronic value will be estimated by dividing the subchronlc value by 10 or less. This 1s supported experi- mentally by Ue11 and NcColllster (1963) and HcNamara (1976). 07218 -3- 03/11/85 ------- MATIMO VALIItl FOR DOSES i It t •- > 2 P J- I 1 t • It IF IN MED < -3 • -I.BtofMCD • •• IF-J < tafMtD < S MVj • 1 IPfefMfD > J -3-1-1 t I ? bfl NUMAM MED linffM*! I S I 4 o OD \ O oo OS FIGURE 2-1 Rating Values for Doses used (o Rank Chronic ToxUtty ------- TABU Z-1 Rating Values for HOAEls. LOAEls and fCls used to Rank Chronic Toxlclty Mimo tmcT 1 f NfVMf INDUCTION Ofl OTHER BIOCHEMICAL CHANGE WITH MO PATHOLOGIC CHANGES AMD NO CHANGE IN ORGAN WEIGHTS. t BUT NO OTHER APPARENT EFFECTS. WCKWSANWfWMTl. • IllVtHtiett CltiULAH CHAMOtit CtOUOY HittitHO.KYOHOftCCMAIIOt.OH MTTYCHAIHm, f NTCflOftt.ONMfTAHAilAiriTNNOA^AMEI^OfCtltMemOfOiraAMnMCTIOM. AMV NEUROPATHY WITHOUT AIT A fit NT BEHAVIQUAL. SENSORY. ON fHYSIOlOOIC CHANGES. f Nf CROStf. ATHOWV. MWCMTflOHIV. ON M^TAM. AST A WITH A Of ft CT AW. I Of CUE «f NT Of ORGAN FUNCTION*. ANY NEUROPATHY WITH A MEASURABLE CHANGE IN BEHAVIORAL. SENSORY. OR fHVSIOLOGIC ACTIVITY. • NECROSIS. ATROPHY. HVFff RTMOmV. ON Kit TAW. ASIA WITM Df nWtTVf ONOAN UVSff UNCTION. ANY NEUROPATHY WITH GROSS CHANOIS IN BEHAVIOR. SCNSOBV.ON MOTOR PEREORMANCE. ANY DECREASE IN REPRODUCTIVE CAPACITY. ANY EVIDENCE O? FETOTOKICITY. • f -.PRONOUNCED PATHOLOGIC CHANGES WITH WVtRE ORGAN OVTOJNCTfON . ANY NEUROPATHY 'WITH LOSS or BEHAVIORAL OR MOTOR CONTROL ON LOSS OP si NSORV ABILITY. REPROOUCTTVI DYSFUNCTION. ANY TERATOOENIC EFf-ECT WITH MATERNAL 1ONICITY. ft DC ATM ON PRONOUNCED LIFE SHORTENING. ANY TERATOOENIC f ffECT WITHOUT PONS Of g MATERNAL TOKICITV. o CD ------- 4. The «Ds based on animal data -ni. .*. Put KO in units of »g/day for a 70 kg man.* 5 Assign a dose rating value (IV,) to the dose associated with the KO as described In Figure 2-1. 6 Assign an effect rating value (RVe) to the effect associated with the "ED »s described In Table 2-1. 7. Calculate the CS as: CS ,. „ „. than on, K» C be selected D» the fellowln* . If adequate cnronlc dit. are available. «1sr«g.rd based on subchronlc data. . If .ore than one HCD remains, select the BED uhlch 1s based on the 'best' data. for a given route will be used. .." -Hh the hlgheS, CS. »s detailed 1. the f.IMm .«"-. «.1.» «U«1f1«.«". «he^ has r«.lt ,d ,„ a reasonable 41.tr1k.t1. .f CSs for the compounds thus far animal dose (mg/day) x ( an1mal weight .It the animal dose 1s In.-gAg/day the^uman .dose In^g/da, equals: x 70 kg. animal dose (mgAg/day) x 11/02/84 07218 ------- 10 The RQs are then assigned based on the following relationship to CS: Composite Score *Q 81-100 I 41-80 10 21-40 100 6-20 1000 1-5 5000 As detailed 1n the following section, this classification scheme has result- ed 1n a reasonable distribution of RQs for the compounds thus far analyzed. 0721B -7- 09/19/84 ------- 3. APPLICATION OF THE «THOOOl06Y To date. -260 compounds have been assessed using the methodology described in Chapter 2. In the final evaluation. Insufficient data were available to derive CSs on 81 cot-pounds. CSs were derived by analogy for 47 conpounds. and CSs were directly derived from experimental data on the 116 remaining compounds. Histograms were constructed from preliminary evalua- tions showing the distribution of RVds. RVes and maximum CSs. and are given 1n Figures 3-1. 3-2 and 3-3. respectively. Although the final evalua- tion has changed several totals, the discussions concerning these histograms and. more Importantly, the conclusions reached are the same. A reasonably symmetric distribution of CSs -as obtained (see Figure 3-3). Histograms of the RVds and RVes were generated to better under- stand the distribution of CSs and to suggest ways in which the methodology could be modified to account for the available data. As Indicated In Figure 3-1. the distribution of RVds 1s skewed, markedly toward the lower values. While this partially reflects the distribution of doses In all the available data, many of the doses given an RV, of 1 were well In excess of 1000 mg/day. suggesting that U may be desirable to expand the RVd scale, at least at the lower limit. In the distribution of RVes. the predominance of RVes of 10. which indicate mortality or teratogenlc effects without signs If maternal toxldt'y. appears to reflect the nature of the data on the 105 compounds and may not be of substantial use In modifying the effects rating scheme. All RVfts derived for the "lOS compounds, not Just those associated with the maximum CS. are being reanalyzed to better evaluate this assertion. . 09/19/84 07218 ~B" ------- 10- FIGURE 3-1 Distribution of RVds In Raxlmum Composite Scores for 105 Compounds 0721B -9- 09/19/84 ------- i i !•«••• 7. ••« FIGURE 3-2 Distribution of RV s 1n Haxlmun Composite Scores for 105 Compounds 0721B -10- 09/19/84 ------- 1- u.16 21-2S 10-20 11-3S 41-45 >K> S8-40 «f-K FIGURE 3-3 ComposUe Scores for 105 Compounds 0721B -11- 09/19/8* ------- In addition to examining the distribution patterns of CSs, RV.s and RV s. 1t was also determined If any correlation existed between reported- acute and calculated-chronic toxlclty values and if any structural correla- tions could be found vs. the chronic toxlclty values. These determinations were deemed Important since acute mammalian toxlclty 1s a primary criterion In establishing toxlclty rating schemes, and the Inclusion of chronic toxl- clty might possibly be redundant. This latter concern Is possibly justified given the relationships between acute and chronic toxUUIes noted by HeNamara (1976). Well and HcColllster (1963) and Ue1l et al. (1969). Conse- quently, for the 105 compounds on which maximum CSs were directly derived, the LOcQ 1n experimental mammals was Identified from the Registry of Toxic Effects of Chemical Substances (NIOSH, 1982) and converted to approximate human LDc.s using the cubed root of the body weight ratios as specified In point 4, Chapter 2. Preliminary results of these analyses are given 1n Figures 3-4. 3-5 and 3-6 for aromatic*.^aliphatic* and Inorganics, respec- tively. Although an attempt 1s being made to more critically review the acute toxlclty data, and statistical analyses will be conducted, no correla- tions between maximum CSs and minimum LD,Qs are apparent. That 1s to say, the chronic toxlclty of a series of chemicals cannot necessarily be pre- dicted from acute toxldtles. This Is a well established principle In the j field of toxicology. Therefore, the use of chronic toxlclty as a ranking tool Is not redundant. Although work on structural correlations Is In a very preliminary stage, Figure 3-7 Indicates no apparent correlation between maximum CSs and Upo- phllldty for 21 substituted benzenes. In this figure, log of the octanol/ water partition coefficient given by Hansch and Leo (1981) was used as the Index of I1poph1l1c1ty. Analyses of other structural parameters are currently being conducted. 0721B -12- 09/19/84 ------- » i.O-i 4.0-1 J.I-I 2.0 H i.o H o.sH e • A A e CHicmo • MITKO A OTHER ~T i i 10 20 ao MAXIMUM COMPOSITE SCORE AROMATICS 10 FIGURE 3-4 Composite Scores vs. H1n1«i» LD5(,s for 28 Aromatic Compounds 07218 -13- 09/19/84 ------- I f 0-, 4.0- .... 3.0- 2.8- f I 2.0- o o - 1.0- O.i- • CMLORD o OTHER 10 20 30 COMPOSITE SCORE ALIPHATIC* T 40 n •0 FIGURE 3-5 Composite Scores vs. MlnlM- Utf for 33 Aliphatic Compounds 0721B -14- 09/19/84 ------- I 4.0i I.S- 3.0- 2.5- 2.0- 1.5- 1.0- 0.5- I 10 T 20 1 30 I 40 I K COMPOSITE SCORE INORGANICS FIBURE 3-6 Composite Scores vs. (Un^mum LDq_s for. 25 Inorganic Compounds 0721B -15- 09/19/84 ------- i n- n- t- i i I • MGURE 3-7 ComposUe Scores vs. Log P for ?1-Substituted Ben/enes ------- 4. SOME CONCEPTUAL CONSIDERATIONS The development of the quant Hat We rating scheme for effects (see Table 2-1} and the combination of this scheme with a quantitative estimate of dose (see Figure 2-1) represent a potentially useful Innovation 1n the analysis and assessment of chronic toxlclty data. The effects rating scheme 1s based on a combination of biochemical, hlstologU. physiologic and gross effects arranged 1n Increasing order of severity. While the rating values assigned to each type of effect are essentially arbitrary, rating values of 1 to 3 or 4 have been generally regarded as NOAELs, 5-7 as LOAELs and 7-10 as FELs. In an attempt to allow for the necessary scientific judgment, the descrip- tion of the effects Is Intentionally not too detailed. Although some addi- tional modifications and expansions of the scheme may be desirable, the application of the scheme to date suggests that It would be a mistake to attempt to catalogue every possible specific effect which chemicals can Induce and to associate each effect with a quantitative value. Also, the ^ ^ ranking scheme Is not organ specific. While the ICRP (1977. 1979) has addressed the problem of organ sensitivity to specific radlonuc.Hdes. and their approach nay be useful In predicting the most sensitive organ for cer- tain radlonucUdes, the effects rating scheme presented 1n Table 2-1 Is Intended to be applicable across target sites. Nonetheless, the variation In organ sensitivities 1s an Important factor In defining the BED associated with a given dose level for a particular toxicant. This 1s Illustrated In Figure 4-1, hypothetical data 1n which NOELs. NOAELs. LOAELs and FELs are plotted on a RVd vs. RV£ diagram. At low doses (I.e., high RV s) only NOELs are observed. As the dose In- creases (I.e.. the RV^ decreases) effect ratings become Increasingly high. 07218 -17- 09/19/84 ------- ECIESAMD tOAIL * NOAEL V 1- MOEL FIGURE 4-1 Hypothetical MOELs. HOAELs. LOAELS and FELs 0721B .18- 09/19/84 ------- However, at a gl«n «f'«t level, ~Utpl. points can b« e.pected a, the „„« increases -1th the point furthest to the right representing the »«t ,,r,s1t1« organ or species or 1r.cr.as1n, Incidence of the tfftel. The slope „, the Hn, oravn to the right of the effect I...1 P«'nts an. l.l.r,Ktl.g the .-axis to the left of the .OILS represents the 1.1— '«'"» " *»« S,«r1t, of effect .Hh Increasing dose and «» be »«-d the apparent ,e«r1t, slope. Ho«..r. as Illustrated In ,**. M. the apparent sever- uy .Lp. «y »e a composite of .wtrll, slopes for specific organs and/or spedes. ,a 09/19/84 07218 -19' ------- TftUE CUKVES rOM PEMENTOHC Oft SPECIES MED CURVE FIGURE 4-2 Apparent BED Curve as a Composite of True Curve for Different Organs or Species 0721B -20- 09/19/84 ------- 5. MOIFICATION AND APPLICATIONS The basic methodology outlined 1n Chapter 2 of thU report was developed In response to a specific need. Having applied the methodology to -260 compounds, explored some of the conceptual considerations Inherent 1n the methodology, and received preliminary comments from scientists both within and outside of the Agency, the following modifications have been considered: 1. Derive the CS as the SUB rather than the product of RVd and RVe. 2. HodUy the dose rating scheme to cover a wider range of doses. As Indicated 1n Figure 3-1 and discussed 1n Chapter 3 of this report, several studies from which maximum CSs were derived Involved dose levels well 1n excess of 1000 mg/day. yet were still assigned the minimum RVd of 1. The revision currently under consideration would cover 10 log dose units from 10* mg/day yielding an RVd of 1 to 10'- mg/day yielding an RVd of 10. 3. Review and utilize data on pharmacok1net1cs and other relevant data to obtain more reasonable estimates of absorption from oral and Inhalation routes. Th5 -current approach assumes 50% absorption from Inhalation exposures and 100X absorption from oral exposures. These assumptions were made rather than review- Ing absorption data In an effort to minimize the cost of this project. However, these assumptions may be misleading particu- larly for metals. 4. Modify the effects rating scheme giving more specific guidance and/or altering some of the criteria. In addition, the application of the methodology has suggested that the RV vs. RV plot may be useful to other Agency Offices 1n the estimation e ' d of NOELs or NOAELs- used 1n the derivation of ADIs. Kushner et al. (1983) have recently reviewed the use of AOIs 1n Superfund Implementation, and Stara and coworkers (Stara et al.. 1980, 1981; Oourson and Stara. 1983) have reviewed more general problems with the estimation and application of ADIs In the regulatory process. Two problems Involving the use and derivation of AOIs may be at least partially alleviated by using the RVd vs. RVg plot. 0721B .21- 09/19/84 ------- First, the Agency frequently has been criticized for not using all of the available data 1n estimating the NOAEL from which ADIs are derived. Using the RV vs. RV, plot along with an appropriate statistical method for estimating the apparent severity tlope and the ^-Intercept (I.e., maximum NOEL), all of the available subchronlc and chronic data could be used. Second, examples have been encountered where no suitable NOAELs or LOAELs are available from which an ADI could be derived. In such cases, data on FELs and NOELs could be used to estimate either the maximum NOEL or a suit- able NOAEL (e.g., dose associated with an RVg of 1 or 2). Again, this would be dependent on the development of an appropriate mathematic model to estimate the severity slope and x-1ntercept. In addition to these Immediate applications, U may be desirable to con- sider expanding the RV, and RV plot to Include axes for duration of exposure, species and Incidence of response. This, however, would be a very complex undertaking that should await further development and applications of the basic RVft vs. RVd plot. 0721B -22- 03/11/85 ------- 6. REFERENCES Dourson, H.L. and J.F. Stara. 1983. Regulatory history and experimental support of uncertainty (safety)' factors. Reg. T.«1c.1. Pharmacol. 3: 224-238. Hansch, C. and A.J. Leo. 1981. Pomona College Medicinal Chemistry Project. Seaver Chemistry Laboratory. Claremont, CA. ICRP (international Collision on Radlologlc Protection). 1977. Recommen- dations of the international Contusion on radlologlc protection. ICRP Pub.l. 26. Pergamon Press. Elmsford, NY. p. 50. ICRP (International Comlsslon on Radlologlc Protection), 1979. -Radio-' nucllde release Into the environment: Assessment of doses to man. ICRP Publ. 29. Pergamon Press. Elmsford. NY. p. 76. Ku.hn.r; L.H.. «.C. Wards and V. Pong. 1983. The potential use of the ADI in Superfund Implementation, mtre Corporation. McLean. VA. p. 68. Samara. I.P. 1976. Concepts 1n health evaluation of commercial and industrial chemicals. In: New Concepts 1n Safety Evaluation: Advances in Modern Toxicology. 1(1): 61-115. NIOSH (National Institute for Occupational Safety and Health,. 1982. Registry of Toxic Effects of Chemical Substances. U.S. DHE«. Cincinnati. OH. ,, 03/11/85 0721B •"' ------- Stara, J.F., D. Kello and P.R. Durkln. 1)80. Human health hazards associ- ated with chemical contamination of aquatic environment. Environ. Health Perspect. 34: 145-188. Stara, J.F., H.I. Dour son and C.T. DeRosa. 1981. Water quality criteria: Methodology and applications. In: Conference Proceedings: Environmental Risk Assessment: How New Regulations will Affect the Utility Industry. Electric Power Research Institute. Palo Alto, CA. U.S. EPA. 1980. Guidelines and methodology used In the preparation of health effects assessment chapters of the consent decree water quality criteria. Federal Register. 45: 79318-79379. Hell, C.S. and D.O. HcColHster. 1963. Safety evaluation of chemicals. Relationship between short- and long-term feeding studies 1n designing an effective toxUUy test. Agrlc. Food Chen. 11: 486-491. Well. C.S.. H.O. Uoodslde, J.R. Bernard and C.P. Carpenter. 1969. Rela- • tlonshlps between slngle-peroral. one-week, and ninety-day rat feeding studies. Toxlcol. Appl. Pharmacol. 14: 426-431. 07218 -24- 09/19/84 ------- |