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feature anoverview of setting occupational exposure limits oels for pharmaceuticals setting appropriate occupational exposure limits is an integral component in assuring the health and safety of workers byrobert h ku ...

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            FEATURE
            Anoverview of setting
            occupational exposure limits
            (OELs) for pharmaceuticals
            Setting appropriate occupational exposure limits is an
            integral component in assuring the health and safety of
            workers
            ByRobert H. Ku                             Since adhering to OELs is consid-       testing for the toxicity of chemicals
                                                     ered an effective and proven way to       became more common and more epi-
            INTRODUCTION                             protect workers from the deleterious      demiologic studies were done in
                    ccupational exposure limits      health effects caused by chemicals,       workplaces, the approach used to set
                           1                         many pharmaceutical companies have        OELswasbasedonthe“no-observed-
                    (OELs) for the protection of     opted to determine OELs for their drug    effect-level/safety factor” (NOEL/SF)
            Oworkershavebeenaroundat                 substances for internal use.              approach.1 In this approach, all of the
            least since 1939 when the National         OELs, if appropriately determined       pertinent animal and humanstudiesare
            (later changed to American) Confer-      and periodically monitored in the         reviewed and the highest dose that did
            ence of Governmental Industrial Hy-      workplace air, would offer a first line    not cause an effect in the most sensitive
            gienists (ACGIH) published its inau-     indication of whether exposures are       health end point (the NOEL) is identi-
            gural acceptable workplace exposure      acceptable or not. The challenge to       fied.2 Once a NOEL has been identi-
            limits (now known as threshold limit     toxicologists and other health profes-    fied, a set of uncertainty (or safety) fac-
            values, or TLVs). In 1970, the U. S.     sionals involved in setting OELs is to    tors are applied to this value to
            Occupational Safety and Health Act       determine a value that has an ade-        accommodate limitations in the data
            incorporated by reference the 1968       quatemarginbetweenalevelthatpro-          and to try to assume that workers are
            ACGIH TLVs as enforceable limits.        duces undesired health effects and        protected.
            The Occupational Safety and Health       one that does not. This is the safety       Thenumberandmagnitudeofthese
            Administration   (OSHA) refers to        margin. If an OEL is set with an inor-    safety factors depend on the quality of
            these enforceable limits as permissible  dinatelylargesafetymargin,thenvalu-       the data. In general, some of these
            exposure limits (PELs).                  able resources may be expended un-        safety factors may include: (1) a factor
              Most TLVs and PELs are for com-        necessarily in the form of extensive      from 1 to 10 for animal-to-human (in-
            monly   used   industrial  chemicals     engineering containment equipment         terspecies) extrapolation (if the NOEL
            where a large number of workers po-      or overly protective personal protec-     is based on animal data), (2) a factor
            tentially may be exposed. Very few       tive equipment. If an OEL is set too      from 1 to 10 for human-to-human in-
            pharmaceuticals fit this description,     high, then employee health may be         traspecies variability in response, (3) a
            hence, very few pharmaceuticals are      compromised.                              factor from 1 to 10 to consider study
            on the ACGIH list of TLVs or the           This article provides an overview of    duration (a long-term study being
            OSHAlist of PELs.                        howOELshavebeendeterminedhis-             morehelpfulthanashort-termstudy),
                                                     torically, new approaches that are on     (4) a factor to consider the persistence
            Robert H. Ku, Ph.D., D.A.B.T.,           the horizon, and approaches that are      of the drug in the body (or elimination
            C.I.H., is a Principal Toxicologist      unique to pharmaceuticals.                half-life), and (5) a factor to accom-
            with SafeBridge Consultants, Inc.,                                                 modate for absorption efficiency by
            Mountain View, California (e-mail:                                                 different routes of exposure.2–4
            robert.ku@safebridge.com).               APPROACHESTOSETTINGOELS                     If a NOEL is not available, then a
            SafeBridge has expertise in              The historical approach used to set       lowest-observed-effect-level (LOEL)
            occupational and environmental           OELs was based on human experi-           can be used The LOEL is the lowest
            toxicology, industrial hygiene, and      enceintheworkplace.Ifairbornelev-         level that causes an effect in the most
                                                                                                                   3
            analytical chemistry, and                els of a chemical were causing adverse    sensitive end point.  A safety factor
            specializes in providing these           health effects, then these levels were    from 1 to 10 may be considered for
            services to the pharmaceutical/          reducedtoalevelthatdidnotproduce          extrapolating a LOEL to a NOEL.
            biotech industries (Web site:            adverse health effects. In the latter     Whetherthesafetyfactoriscloser to 1
            safebridge.com).                         half of the 1900s, as laboratory animal   or closer to 10 depends in part on the
            34   ©Division of Chemical Health and Safety of the American Chemical Society                         1074-9098/00/$20.00
                 Published by Elsevier Science Inc.                                                           PII S1074-9098(99)00070-2
            severity of the end point. For example,     LINEARIZED MULTISTAGE (LMS)                LMS or any other mathematical
            if the adverse health effect is consid-     MODELFORCARCINOGENS                        model for carcinogenic drugs when
            ered serious (e.g., severe birth defect)    WhentheNOEL/SFapproachwasin-               setting OELs. It has preferred to con-
            then a factor closer to 10 may be more      troduced, it was applied to all chemi-     tinue to use the NOEL/SF approach
            appropriate; if the adverse health ef-      cals. This approach assumed that if        for all chemicals and simply consid-
            fect is considered minor (e.g., de-         exposure to a chemical was kept be-        ered cancer as a severe adverse health
            creased body weight) then a factor          lowsomelevel(e.g.,athresholddose),         effect. Alternatively, some companies
            closer to 1 may be more appropriate.        noadverse effects would occur. How-        have adopted approaches to manage
              The NOEL or LOEL is dependent             ever, as more information became           worker exposure by recommending
            on the number of test subjects used         available on the biologic mechanism        specific personal protective equip-
            and the doses selected in the studies.      of action of carcinogens (vs noncar-       ment and requiring handling proce-
            Thegreaterthenumberoftestsubjects           cinogens), there was a concern that a      dures be followed. This approach is
            pergroup,thegreaterthelikelihoodof          cancer risk may exist at any level of      based on the job assignment and po-
            observing an effect. The number of          exposure. In other words, contrary to      tential  for  exposure (e.g., perfor-
            doses used per study is frequently lim-     noncarcinogens, where a threshold          mance-based exposure control levels)
            ited, to 3 or 4 dose levels. If the doses   dose was believed to exist, there was      in lieu of setting OELs.
            are properly chosen, one of the doses       nodoseofacarcinogenthat was con-
            will turn out to represent the NOEL,        sidered without risk (i.e., no threshold
            andanother,theLOEL.However,the              dose). Because testing at very low         BENCHMARKDOSEAPPROACH
            true NOEL or LOEL will probably be          doses and with a large number of an-       Recently, a new approach has been
            somewhere in between these two              imals was not possible or practicable,     proposed for setting acceptable expo-
            tested dose levels. If the gap between      mathematical models were developed         sure limits called the benchmark dose
            these two tested dose levels is large,      to try to predict the hypothetical in-               8
                                                        cremental cancer rate at these very        approach. For noncarcinogens, this
            then there could be greater uncer-          low doses. The model that was ulti-        approach attempts to identify a dose
            tainty as to what the true NOEL or          mately adopted by government agen-         that corresponds to a measurable re-
            LOELmaybe.                                  cies was the linearized multistage         sponse rate (e.g., dose that results in a
              An equation that is used to deter-                                                   10%responserate,orED                  -
                                                        (LMS) model. This model essentially                                  10). This des
            mine an OEL for a chemical can be           resulted in a linear dose-response re-     ignated response rate also has been
                                   5
            represented as follows :                    lationship at very low doses while ac-     termed the “point of departure.” In es-
            OEL5@~NOEL!                                 comodating for the observable dose-        sence, the point of departure replaces
                                                        response relationship at the high          the NOEL or LOEL. The point of de-
               3~humanbodyweight!#/                     doses tested. All that was needed now      parture is preferred over the NOEL or
                 @~safety factor!n                      wasforgovernmentagenciestodecide           LOEL in that it represents a dose that
               3~humanbreathingrate!#                   what the acceptable cancer risk            corresponds to a specific and measur-
            NOELusually is in units of milligram        shouldbe.Fortheprotectionofpublic          able response rate.
            of chemical administered/kilogram of        health, the U.S. Environmental Pro-          Thebenchmarkdoseapproachthen
            animal body weight/day.                     tection Agency has set the acceptable      requires an estimation of exposure in
                                                                                     25            the most heavily exposed individuals.
              Humanbody weight typically is as-         cancer risk at around 1 3 10    to 1 3
                                                        1026 (one in one hundred thousand          Theratioofthedosecorrespondingto
            sumed to be 70 kiligrams for an adult       to one in one million) for potential       the point of departure and exposure
            male.                                       exposure of individuals to chemical        estimate in the most heavily exposed
              Safety factors are numeric values for     carcinogens in the environment. The        individuals becomes an indicator of
            accomodating limitations in the data,       dose that corresponded to the ac-          acceptability and has been termed the
            as described above.                         ceptable cancer risk based on the          marginofexposure(MOE).Thelarger
              Breathing rate in workers typically       LMS model became the acceptable            the MOE, the less likely that an ad-
            is assumed to be 10 m3                -
                                    /8-hour work        exposure limit.                            verse effect will occur. There is still
            day.                                          Some     researchers   found     that    debate over the upper limit of the
              Hereisanexampleofthisapproach             ACGIHsTLVsforcarcinogens(deter-            MOE(e.g., 10, 100, 1000) to be con-
            for the synthetic estrogen, ethinyl es-     mined by approaches other than the         sidered acceptable.
            tradiol. The NOEL in humans has             LMS approach) corresponded to ap-            One criticism of the LMS model is
            been estimated to be around 3.5 mg/                                23                  that all carcinogens are treated the
                                                        proximately a 1 3 10       cancer risk
            day. (Because it is reported in these                               6                  sameway.Butasmorebecameknown
                                                        using the LMS model. Others have
            units, there is no need to multiply by the  inferred that this cancer risk repre-      about the mechanism of action of car-
            human body weight). If one assumes a        sented OSHA’sacceptablecancerrisk          cinogens, it appears that there may be
            safety factor of 10 for the human vari-     policy and believe this is the appropri-   at least two general groups, threshold
            ability in response and a breathing rate                                          7    dose and nonthreshold-dose carcino-
                                                        ate cancer risk level to use for workers.
            10m3
                  /8-hourworkday,thentheOELis             The pharmaceutical industry with         gens. Under the benchmark dose ap-
                                        3
            estimated to be 0.035 mg/m .                some exceptions has not adopted the        proach, threshold-dose carcinogens
            Chemical Health & Safety, January/February 2000                                                                            35
             are treated similarly to non-carcino-          tionally and for which an OEL is in-            the drugs are related to its pharmaco-
             gens.                                          tended? If not, then one must con-              logical mechanism of action. As the
                For   nonthreshold-dose       carcino-      sider   the    possible    difference   in      saying goes, “The dose makes the poi-
             gens, a straight line is drawn from the        bioavailability. For example, alendro-          son.” What may be therapeutic at a
             point of departure to the origin. The          nate is a bisphosphonate drug ap-               low dose may cause serious toxici-
             acceptable exposure limit is deter-            proved for osteoporosis and for other           ty at a high dose. For drugs where
             mined for any acceptable response              bonediseases.Itisadministeredorally             the mechanism of toxicity is related
                               26                           and has a bioavailability of less than          to exaggerated pharmacology, then
             rate (e.g., 1 3 10   ) belowthepointof
             departure. Thus, the benchmark ap-             1% orally. If this drug is readily ab-          by protecting a worker against the
             proach attempts to address a major             sorbed through the respiratory tract,           “normal” pharmacologic effects of
             shortcoming of the LMS model, by               thenthe100-foldsafetyfactormaynot               the drug also will also protect
             treating threshold- and non-thresh-            be adequately protective. Unfortu-              against the “exaggerated” or adverse
             old-carcinogens differently.                   nately, it is often the case that for           effects of the drug.
                                                            drugs that are not intended for admin-            There are other drugs where toxic
                                                            istration by the inhalation route, no           effects are unrelated to the mechanism
             APPROACHESSPECIFICTO                           inhalation bioavailability data may be          of  pharmacologic action. For in-
             PHARMACEUTICALS                                available. To be conservative (i.e.,            stance, a drug may cause developmen-
             Pharmaceuticals are chemicals. How-            most health protective), one may as-            tal toxicity (i.e., birth defects) or can-
             ever, they differ from most industrial         sume that the inhalation bioavailabil-          cer by a mechanism unrelated to its
             chemicals because there often is a             ity is complete (i.e., 100%). Then, if          pharmacologic effects. In these cases,
             wealth of human data available on              the oral bioavailability of the drug is         using the 100-fold safety factor on the
             pharmaceuticals. In setting OELs for           1%, an additional safety factor of 100          therapeuticdosemaystillbeappropri-
             certain pharmaceuticals, some have             may be needed to accommodate for                ate, but would need to be used with
             proposed simply to divide the thera-           this difference in bioavailability by           greater caution. If a promising drug
             peutic dose by a safety factor. For cer-       these two routes. If the oral bioavail-         causesbirthdefectsnearthetherapeu-
             tain pharmaceuticals that mimic some           ability is closer to 100% (or closer to         tic dose range, then its likelihood of
             biologic activity of a chemical pro-           the inhalation bioavailability), then a         ever reaching the marketplace (and
             duced by the body, some have pro-              smaller bioavailability adjustment fac-         thus manufactured in large quantities)
             posed limiting exposure to a fraction          tor may be considered.                          is small. However, teratogenic drugs
             of this endogenous biologic activity.             A second issue to note when con-             couldmakeitintothemarketplaceif
             Both of these approaches actually are          sidering applying the 100-fold safety           thedrugisintendedforolderwomen
             similar to the NOEL/SF approach de-            factor to the lowest recommended                (i.e., those past menopause) or for
             scribed above.                                 therapeutic dose is the intended use of         men.
                                                            the drug. If a drug is intended to be             In summary, applying the 100-fold
                                                            usedinlife-threateningdiseaseswhere             safety factor to the lowest therapeutic
             THERAPEUTICDOSE/SAFETY                         significant toxicities may be consid-            dose is simple to do. However, there
             FACTORAPPROACH                                 ered acceptable, the 100-fold safety            are a number of issues that must be
             In the therapeutic dose/safety factor          factor may not be adequately protec-            considered to determine whether
             approach, the lowest recommended               tive. Less than life-threatening side ef-       this method is appropriate. These in-
             therapeutic dose of the drug is identi-        fects may be acceptable to the patient          clude:
             fied. This therapeutic dose then is di-         when trying to save the patient’s life,
             videdbyasafetyfactor.Asafetyfactor             but these same side effects are not ac-         1. the difference in bioavailability be-
             of 100 usually is suggested because it         ceptable to healthy workers. Clearly,              tweentherouteofdrugadministra-
             can be thought of as a factor of 10 for        the 100-fold safety factor approach for            tion and the inhalation route, the
             adjusting a therapeutic effective dose         ananticancerdrugwhereheroicdoses                   route by which workers are ex-
             to a therapeutically noneffective dose         may be needed to save the patient of-              posed;
             (somewhat similar to adjusting a               fers less protection than for an anti-          2. the intended use of the drug or
             LOELtoaNOEL)andafactor of 10                   cough drug where the effects of the                risk-benefit    considerations     (i.e.,
             to accommodate for individual vari-            disease are not life-threatening and               whether it is for serious or life-
             ability in response.                           may merely be a temporary nuisance.                threateningsituations or for less se-
                For many drugs, this approach may           Whatever side effects are produced                 rious diseases); and
             be reasonable and has produced                 from an anticough medication ought              3. possible differences in the mecha-
             OELs similar to the traditional                not to cause any side effects more un-             nism of action for the therapeutic
             NOEL/SFapproachdescribed above.                comfortable than the cough itself. In              effects versus the toxic effects.
             This approach cannot be used indis-            the case of anticough medication, the
             criminately, however, for several rea-         100-fold safety factor approach may             Using ethinyl estradiol as an example
             sons. First, is the drug administered          be overly conservative.                         here, the lowest therapeutic dose is
             throughtherespiratorytract,theroute               Another issue to consider is to de-          around 20 mg/day. Dividing by the
             towhichworkersareexposedoccupa-                termine whether the toxic effects of            100-fold safety factor and the breath-
             36                                                                                Chemical Health & Safety, January/February 2000
                                3                                                                               timated by several approaches, one
              ing rate of 10 m /8-hour workday, the            production rate in women is higher
                                               3                                                                may need to decide the most appro-
              estimated OEL is 0.02 mg/m .                     than the production rate in men.) The
                                                               relative estrogenic potency of ethinyl           priate approach (i.e., the approach on
                                                               estradiol to 17-beta estradiol is around         which the underlying data are most
              INCREMENTALINCREASEOF                            2. Assuming a 1% incremental in-                 solid) especially if the approaches re-
              ENDOGENOUSBIOLOGICAL                             crease in biologic activity from ethinyl         sult in OELs that vary significantly
              ACTIVITY                                         estradiol is deemed acceptable and               (e.g., by orders of magnitude). For the
              More and more frequently nowadays,                                                      3         ethinyl estradiol example, the OEL es-
              drugs are being developed to replace             using a breathing rate of 10 m /8-
              or mimic the function of a substance             hour workday, the estimated OEL                  timated by the three approaches pre-
                                                               for ethinyl estradiol is 0.035 mg/m3.            sented above varied by less than a fac-
              naturally produced by the body. If the                                                            tor of two. When they vary by such a
              levels of these naturally occurring sub-                                                          small amount, the values essentially
              stances are decreased, the risk of cer-          SUMMARY                                          can be considered to be equivalent.
              tain diseases may increase. By supple-           Setting appropriate OELs is an inte-                It should be kept in mind that the
              menting the levels of these naturally            gral component in assuring the health            determination of an OEL for a phar-
              occurring substances with an exoge-              and safety of workers. The approach              maceutical agent or for any other
              nous source, these diseases may be               proposed historically and still most             chemical entity is an inexact science.
              ameliorated or eliminated. This is               commonly used is the NOEL/SF ap-                 Each approach has its own set of as-
              the basis for hormone replacement                proach. In this approach, a NOEL for             sumptions and limitations. It often
              therapy (HRT) in postmenopausal                  the most sensitive effect is identified           comesdowntoprofessionaljudgment
              women.Inthese women, the levels of               and modified by safety factors to ac-             as to which approach is preferred and
              naturally occurring estrogens are re-            commodateforuncertainties and data               how large the uncertainty factor
              duced subjecting them to an elevated             gaps. This approach presumes that                should be. It is important for anyone
              risk of certain types of diseases, e.g.,         both carcinogenic and noncarcino-                whorelies on OELstounderstandthe
              osteoporosis. For individuals who do             genic effects do not occur if exposure           assumptions used in deriving the
              not have a reduced level of estrogens,           is kept below the NOEL. As some ev-              OEL. The real test for finding out
              additional exposure may be undesired             idence suggested that a finite risk for           whether an OEL has been appropri-
              and need to be controlled.                       cancer may exist at any level of expo-           ately set comes from actual workplace
                An approach that can be used for               sure to a carcinogen, the LMS model              experience. The responsibility of toxi-
              determining an OEL for these types of            was developed and adopted for car-               cologists and other health professionals
              drugs is to limit exposure to a level            cinogens. This mathematical model                tasked with setting OELs is to estimate
              where exposure contributes a small               predicted the level of carcinogenic              a value that is protective of workers yet
              fraction, like 1%, of one’s endogenous           risk for any level of exposure. Once an          without being so overly protective that
              biological activity of that substance.           acceptable risk level is specified, the           resources are unnecessarily spent.
              For instance, if the daily production            acceptable exposure level could be
              rate of 17-beta estradiol in the body is         determined. As further information               References
              X mg/day, then the acceptable expo-              about the mechanism of action of car-            1. Lehman, A. J.; Fitzhugh, O. G. Assoc.
              sure could be set at 1% of that rate, or         cinogens became available, it became                Food Drug Off. U. S. Q. Bull. 1954,
              0.01X mg/day. If the drug is not iden-           apparent that NOELs may indeed ex-                  18(1), 33.
              tical to the endogenous substance,               ist for some carcinogens. This resulted          2. Dourson, M. L.; Stara, J. F. Regulat.
              then the relative potencies of the drug          in the development of the benchmark                 Toxicol. Pharmacol. 1983, 3, 224,
              and the endogenous substance also                dose approach. One of the major ad-              3. Baird, S. J. S.; Cohen, J. T.; Graham,
              must be determined to be able to limit           vantages of the benchmark dose ap-                  J. D.; Shlyakhter, A. I.; Evans, J. S.
              exposure to a 1% increase in biologic            proachistoallowforgreaterflexibility                 Hum.Ecol.RiskAssess.1996,2(1),79.
              activity. That is, if the limit is set at 1%     in the determination of acceptable ex-           4. Dourson, M. L.; Felter, S. P.; Robinson,
                                                                                                                   D. Regulat. Toxicol. Pharmacol. 1996,
              of the endogenous biologic activity and          posure limits of carcinogens depending              24, 108–120.
              the drug is 10 times more potent than            onwhatisknownaboutthemechanism                   5. Sargent, E. V.;Kirk, G. D. Amer. Ind.
              the endogenous substance, then expo-             of action. For pharmaceuticals, in addi-            Hyg. Assoc. J. 1988, 49(6), 309.
              suretothedrugmustbelimitedto0.1%                 tion to the approaches described above,          6. Rodricks, J. V.; Brett, S. M.; Wrenn,
              of that of the endogenous substance.             several other approaches have been                  G. C. Regulat. Toxicol. Pharmacol.
                Again, using ethinyl estradiol as an           used to set OELs. For instance, the                 1987, 7, 307.
              illustration, the production rate of en-         use of the therapeutic dose and the              7. Herr, M. L. Amer. Ind. Hyg. Assoc. J.
              dogenous estrogen, 17-beta estradiol,            use of an incremental increase in                   1998, 59, 83.
              has been reported in men to be around            some level of endogenous biologic                8. Benchmark Dose Technical guidance
              70 mg/day. (Using the production rate            activity have been considered as ap-                Document: 1996; U.S. Environmental
                                                                                                                   ProtectionAgency.RiskAssessmentFo-
              inmenismoreprotectivethanusingthe                proaches for OEL determination.                     rum. Washington, D.C.; 1996; EPA/
              production rate in women because the               In the case where OELs can be es-                 600/P-96/002A.
              Chemical Health & Safety, January/February 2000                                                                                            37
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...Feature anoverview of setting occupational exposure limits oels for pharmaceuticals appropriate is an integral component in assuring the health and safety workers byrobert h ku since adhering to consid testing toxicity chemicals ered effective proven way became more common epi introduction protect from deleterious demiologic studies were done ccupational effects caused by workplaces approach used set many pharmaceutical companies have oelswasbasedonthe no observed protection opted determine their drug effect level factor noel sf oworkershavebeenaroundat substances internal use this all least when national if appropriately determined pertinent animal humanstudiesare later changed american confer periodically monitored reviewed highest dose that did ence governmental industrial hy workplace air would offer a rst line not cause most sensitive gienists acgih published its inau indication whether exposures are end point identi gural acceptable or challenge ed once has been now known as thre...

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