150 Human toxicology - PDF document

– Human toxicology Compilation of EU Dioxin Exposureand Health DataTask 8 - Human toxicologyReport produced forEuropean Commission EnvironmentUK Department of the Environment, Transport and theRegions (DETR)October 1999 Task 8 - Human toxicology AEA Technology TitleCompilation of EU Dioxin Exposure and Health Data Customer Customer reference Confidentiality,reproductionRestricted - Commercialsubmitted only on the basis of strict confidentiality.

The contentsmust not be disclosed to third parties other than in accordance withthe terms of the contract. File reference Report number Report status CulhamNameSignatureDateAuthor Reviewed by Approved by Task 8 - Human toxicology AEA Technology assessment of health risk is improved. Over recent years a vast number of research reportsThis report reviews the toxicological effects of dioxins, recent assessments of health risk andskin defects (dermal

toxicity);prevalence of diabetes and increased mortality due to diabetes and cardiovascular diseaseschildren exposed transplacentally to PCBs and PCDFs show skin defects, developmentalthese effects, when considering the complex chemical Task 8 - Human toxicology AEA Technology The resultingA Tolerable Daily Intakerecommended. In common with all recent risk assessments, WHO and IPCS support the useassessment by carefully targeted research into:effect

s in animals;applicability of the TEF concept to the critical effects, i.e. developmental effects of Task 8 - Human toxicology AEA Technology 1.Introduction12.Overview of toxicological and epidemiological studies22.1MODE OF ACTION22.2TOXIC EFFECTS42.2.1Cancer2.2.2Reproductive toxicity52.2.3Neurotoxicity2.2.4Immunotoxicity3Derivation of toxic equivalency factors (tefs)84.Health risk assessment104.1HEALTH RISK ASSESSMENT AND TOLERABLE DAILY INTAKE (TDI

)104.1.1 US Environmental Protection Agency (EPA) 1985114.1.2 Nordic 19884.1.3 WHO 19904.1.4 The Netherlands 1996124.1.5 WHO 19984.2MAJOR GAPS IN KNOWLEDGE155.Conclusions166.Recommendations18 Task 8 - Human toxicology AEA TechnologyPage 1 of 17 1.Introductionhumans. It also seeks to establish whether there is sufficient information available toanimals (i.e. mammals).in turn, be used as a basis for recommending TDIs that will protect humans from the T

ask 8 - Human toxicology AEA TechnologyPage 2 of 17 2.Overview of Toxicological andpotential causative agents.2.1MODE OF ACTIONThe basic influence of a damaging substance on an organism takes place at theact is broadly the same. This is important, because it allows assumptions to be madeIt is generally believed that the toxic effects of dioxins are initiated at the cellularvitamin DThe mechanism of dioxin action via the AhR has, until now, been demon

strated only Task 8 - Human toxicology AEA TechnologyPage 3 of 17 substances with lesser or greater potency than the original chemical. However,chemicals in the environment.Cytochrome P450 induction: Binding of dioxin to the Ah receptor has been shownSex Hormone Effects: Ah and oestrogen receptor pathways.Cancer promotion: TCDD causes liver tumours in animals at lower concentrations than any other man-made chemical. Dioxins are not genotoxic (i.e. do

not initiate cancer development),immune surveillance and cytotoxicity (cellular toxicity). It is generally believed, but Task 8 - Human toxicology AEA TechnologyPage 4 of 17 2.2TOXIC EFFECTSskin defects (dermal toxicity);active);increased prevalence of diabetes and increased mortality due to diabetes and however, that it is not totallyThe most extensive dataset on animal toxicity is available for TCDD. In thewhich may cause similar effects. Task 8 -

Human toxicology AEA TechnologyPage 5 of 17 2.2.1Cancer. The sensitivity to liver tumours in rats iswith TCDDs antioestrogenic (sex hormone) activities.For humans, several epidemiological studies on accidental and occupational exposurebut the low quality and/or power of the studies make them difficult to interpret.cancer, leukaemia and breast cancer in women.Recently, the WHO International Agency for Research on Cancer (IARC) evaluatedstages.2.2.2Re

productive toxicity Carcinogenesis is believed to be a multi-event process, and comprises an initiation phase (such asDNA damage) and a promotion phase in which sequential events advance the probability of producingcancerous cells. Task 8 - Human toxicology AEA TechnologyPage 6 of 17 2.2.3Neurotoxicitydevelopmental effects on cognitive (learning) behaviour have been reported inchildren whose mothers had eaten relatively large quan

tities of Lake Michigan fishcontaminated with PCB. Slightly lower IQ was still apparent at 11 years of age. In athe effects.2.2.4Immunotoxicity Task 8 - Human toxicology AEA TechnologyPage 7 of 17 respiratory infections and otitis (inflammatory disease of the ear). Also, infants fromconsumption of fish from the Baltic Sea (contaminated with dioxins and PCBs) hasPCBs and dioxins, has an increased incidence of infectious disease and otitis in the Task

8 - Human toxicology AEA TechnologyPage 8 of 17 3Derivation of Toxic EquivalencyDioxins occur in widely varying mixtures in the environment. This is because eachare not equally potent, as defined by their ability to cause specific toxic effects inanimals. The potential difficulty this presents, in assessing the likely effect of apotency of each congener as a Toxic Equivalency Factor (TEF). The TEF representsdioxin and assigned a TEF of 1. By summing

the concentrations times the TEF of all(WHO-ECEH) and the International Programme on Chemical Safety (IPCS), initiatedwildlife risk assessment. The recommended TEF-values are given in the Technicalbind to the Ah receptor;after considering all available scientific data;REP (relative potency) as a potency value relative to TCDD obtained in a single Task 8 - Human toxicology AEA TechnologyPage 9 of 17 vivoin vitroin vivoin vitro and/or quantitative str

ucture-activity relationship (QSAR) data.For in vivoeffects.The TEF concept assumes a model of dose additivity. There has been muchan additive model for the prediction of TEQs still seems most plausible, in spite ofTEF concept will result in a great deal of error in predicting the concentrations of PCBs also elicit Ah receptor-mediated responses. As acontribution of PCBs to TEQs exceeds that of the PCDDs and PCDFs.concept is still the most plausible

and feasible approach for risk assessment of Task 8 - Human toxicology AEA TechnologyPage 10 of 17 4.Health Risk Assessmentthe identification of the critical effect, i.e. the most sensitive effect, of thethe estimation of a tolerable daily intake (TDI).In this section different approaches to risk assessment of dioxins, as well as estimationto improve the risk assessment are listed.4.1HEALTH RISK ASSESSMENT AND TOLERABLE DAILYINTAKE (TDI)assessment of

the risk to humans were applied, resulting in various estimates of theMethodEffects (species) US EPAlinearised multi-Cancer (rat). Cancer (rat). 1990 10 pgUF 100 Reproductive andimmune effects (rat, The NetherlandsCognitive development, Developmental effects UF uncertainty factor by which estimated NOAEL or LOAEL is divided to give TDI Task 8 - Human toxicology AEA TechnologyPage 11 of 17 * Calculated on body burden (not dose)4.1.1 US Environmental

Protection Agency (EPA) 1985In a reassessment which has yet to be finalised, the linearised multi-stage model is4.1.2 Nordic 1988animal studies, the critical effects in the low dose range were identified as cancer,10 for interspecies variability and 10 for intraspecies variability. The calculationsrecommendation of a Nordic TEF-scheme.4.1.3 WHO 1990 Task 8 - Human toxicology AEA TechnologyPage 12 of 17 effects in humans, an uncertainty factor of 10

was employed and thus a TDI of 10 pgTCDD/kg body weight was recommended. The consultation further recommendedthat the international toxicity equivalency factors (I-TEFs interim approach for risk management purposes, until adequate data for PCDD andwho are breastfed, since the TDI concept for these substances is based on a lifetimeexcessive weight reduction and transferred to the infant via breast milk.4.1.4 The Netherlands 1996assessment of dioxins,

which was based on developmental effects. The Committee onthe reported animal studies, the Committee made use of extrapolation and safetyno adverse effect level (NAEL) of 2 for experimental animals. The CommitteeLimitation of breast-feeding was not considered to be the right way. Since breast-feeding per se has a positive effect on the development of infants there was seen to beno reason to limit the freedom of parents to chose between breast-feedin

g and formulafeeding for their infant. The Committee deemed that the health risk assessment Task 8 - Human toxicology AEA TechnologyPage 13 of 17 constituted an argument for further reducing existing concentrations, which resultlargely from human activities. Task 8 - Human toxicology AEA TechnologyPage 14 of 17 4.1.5 WHO 1998calculated.interspecies differences in toxicokinetics was not required. However, the estimatedthan animals, still uncertainty r

emains regarding animal to human susceptibilities.Furthermore, differences exist in the half-lives of elimination for the different4.1.6 Discussion Task 8 - Human toxicology AEA TechnologyPage 15 of 17 on the choices of critical effect and uncertainty factors, the recommended TDIs weremore recently, PCBs.of high quality due to the broad range of highly qualified international expertsquantitative risk extrapolation.4.2MAJOR GAPS IN KNOWLEDGEin animals

;applicability of the TEF concept to the critical effects, i.e. developmental effects, Task 8 - Human toxicology AEA TechnologyPage 16 of 17 5.Conclusionswhich they act is broadly the same. This is important, because it allows assumptionsIt is generally believed that the toxic effects of dioxins are initiated by the binding ofexperimentalskin defects (dermal toxicity);active).several species have been shown to be particularly sensitive to TCDD, resul

ting inAt higher exposures, children exposed transplacentally to PCBs and PCDFs show skinnot totallythese Task 8 - Human toxicology AEA TechnologyPage 17 of 17 expressing the toxic potency of each congener as a Toxic Equivalency Factor (TEF).The Toxic Equivalent (TEQ) is the sum of the concentration times the TEF for alltowards setting internationally agreed TEFs, the WHO-European Centre foruncertainties, it was concluded that the TEF concept is stil

l the most plausible andAll risk assessments reviewed here, except the US EPA risk assessment, use the Task 8 - Human toxicology AEA TechnologyPage 18 of 17 6.Recommendationsassessment by carefully targeted research into:developmental effects in animals;applicability of the TEF concept to the critical effects, i.e. developmental effects Task 8 - Human toxicology AEA Technology– Human ToxicologyA.1IntroductionA.2Overview of Toxicological and Epid

emiological StudiesA.2.1Mode of ActionA.2.2ToxicityA.2.3Derivation of Toxic Equivalency Factors (TEFs)A.3GlossaryA.4References Task 8 - Human toxicology AEA TechnologyPage A1 of 17 animal (i.e. mammalian) and epidemiological humanA.2.1 MODE OF ACTIONIt is generally believed that the toxic effects of dioxins are initiated by the binding of theA.2.1.1 Aryl Hydrocarbon Receptorthey act is broadly the same. This is important, because it allows assumption

s of effects fornucleus. When heterodimerized with the Ah receptor nuclear translocator protein (Arnt), the Task 8 - Human toxicology AEA TechnologyPage A2 of 17 initiate transcription of specific genes. This mechanism of action of TCDD parallels in manyways that of the steroid hormones. However, dioxin and steroid hormone receptors (e.g. and retinoic acid receptors)metabolising enzymes (Okey A.2.1.1.1 Cytochrome P450 inductionanimals (van Birgelen

Task 8 - Human toxicology AEA TechnologyPage A3 of 17 polybrominated diphenyl ethers and polycyclic aromatic hydrocarbons (PAH). In addition, itmust be regarded as a biomarker of exposure and not of effect since the relationship betweenenzyme induction and the toxic effects is still unclear. Task 8 - Human toxicology AEA TechnologyPage A4 of 17 There is considerable evidence that TCDD has antioestrogenic properties (for review seecause some of the an

tioestrogenic effects of TCDD at relatively high doses, the critical effectsare probably due to interactions between the Ah and oestrogen receptor pathways (Safe A.2.1.1.3 Cancer promotionDioxins are not genotoxic (i.e. do not initiate cancer development), but both TCDD and othercommunication (de Haan A.2.2 TOXICITYmetabolising enzyme activities. The foetus and the neonatal offspring of several species have Task 8 - Human toxicology AEA TechnologyPag

e A5 of 17 accidentalcardiovascular diseases have been reported (Bertazzi Yucheng adults, accidentally exposed to high levels of PCBs and PCDFs, the chronic1995). At higher exposures, in Yusho and Yucheng children exposed transplacentally to PCBsdataset on animal toxicity is available for TCDD. In the epidemiological studies humans aremechanisms of TCDD (Clark and PCBs show relations to an increased incidence of different tumours, the low quality Tas

k 8 - Human toxicology AEA TechnologyPage A6 of 17 cancer mortality for cancer forms such as rectal cancer, leukaemia and multiple myeloma 15years after the industrial accident with TCDD in Seveso (Bertazzi recent study on Swedish fishermen’s wives support an association between exposure to aRecently, the WHO International Agency for Research on Cancer evaluated the available datathis receptor is highly conserved in an evolutionary sense and fun

ctions the same way in PCBs can demasculinized and feminized (Mably Also in humans the developing foetus and infant have been shown to be more sensitive to Task 8 - Human toxicology AEA TechnologyPage A7 of 17 Yucheng children were caused by accidentally high exposure situations to PCBs and PCDFs.cognitive behaviour have been reported in children whose mothers had eaten relatively largeassociated with slightly lower IQ, still apparent at 11 years of

age (Jacobson PCB and TCDD equivalents (TEQ) in mother's milk were negatively correlated with neonatalhigher levels of planar PCBs in breast milk (Huisman quantities of dioxin and/or PCBs transferred to the infant postnatally via breast-feeding,effects were primarily associated with Task 8 - Human toxicology AEA TechnologyPage A8 of 17 incidences of respiratory infections and otitis (Rogan fish from the Baltic Sea (contaminated with dioxins and PCBs

) has been related to an alteredfold higher incidence of infectious disease and otitis in the first year of life than individualsA.2.3 DERIVATION OF TOXIC EQUIVALENCY FACTORS (TEFS)in vitroin vivostudies. This approach is useful, but has its limitations due to a number of simplifications.International Programme on Chemical Safety (IPCS), initiated a project to create a data base Task 8 - Human toxicology AEA TechnologyPage A9 of 17 containing informa

tion relevant to the setting of TEFs. Based on the available information,WHO gathered a group of experts to assess the relative potencies and to derive consensusTEFs for PCDDs, PCDFs and dioxin-like PCBs (Ahlborg et al. 1994, van den Berg et al.1998). In 1997 the WHO expert meeting derived consensus TEFs for both human and wildliferisk assessment (van den Berg et al. 1998). The recommended TEF-values for humans aregiven in Table A1. Task 8 - Human t

oxicology AEA TechnologyPage A10 of 17 bind to the Ah receptor;all available scientific data.REP (relative potency) as a potency value relative to TCDD obtained in a single in vivoin vitroin vivothan in vitro and/or quantitative structure-activity relationship (QSAR) data. For in vivotoxic effects. It is assumed that the TEFs for the critical toxic effects are similar to those basedlimited number of validation studies using mixtures, an additive mode

l for the prediction ofobserved. It is unlikely that the use of additivity in the TEF concept will result in a great deal PCBs also elicit Ah receptor-mediated responses. As aexceeds that of the PCDDs and PCDFs. Task 8 - Human toxicology AEA TechnologyPage A11 of 17 den Berg PCDD/PCDF congenerTEFPCB congenerIUPAC 2,3,7,8-TCDD13,4,4’,5-TCB810.0001a,b,c,d 1,2,3,7,8-PeCDD13,3’,4,4’-TCB770.0001 1,2,3,4,7,8-HxCDD0.13,3’,4,4’,5-PeC

B1260.1 1,2,3,6,7,8-HxCDD0.13,3’,4,4’,5,5’-HxCB1690.01 1,2,3,7,8,9-HxCDD0.12,3,3’,4,4’-PeCB1050.0001 1,2,3,4,6,7,8-HpCDD0.012,3,4,4’,5-PeCB1140.0005a,c,d,e OCDD0.00012,3’,4,4’,5-PeCB1180.0001 2,3,7,8-TCDF0.12’,3,4,4’,5-PeCB1230.0001a,c,e 1,2,3,7,8-PeCDF0.052,3,3’,4,4’,5-HxCB1560.0005c,d 2,3,4,7,8-PeCDF0.52,3,3’,4,4’,5’-HxCB1570.0005c,d,e 1,2,3,4,7,8-HxCDF0.12,3’,4,4’

,5,5’-HxCB1670.00001a,e 1,2,3,6,7,8-HxCDF0.12,3,3’,4,4’,5,5’-HpCB1890.0001a,c 1,2,3,7,8,9-HxCDF0.1 2,3,4,6,7,8-HxCDF0.1 1,2,3,4,6,7,8-HpCDF0.01 1,2,3,4,7,8,9-HpCDF0.01 OCDF0.0001 Limited data setIn vitro Structural similarity Task 8 - Human toxicology AEA TechnologyPage A12 of 17 Ah receptorAryl hydrocarbon receptor, the receptor in animal and human cells towhich a dioxin molecule binds and initiates gene transcription (alsosomet

imes written as AhR).BiomarkerA biological response to a chemical that gives a measure of exposure,individual sensitivity or toxic effect.Critical effectThe most sensitive effect, i.e. the effect occurring at the lowestDioxin-likeA compound structurally similar to TCDD which binds to AhR andelicit qualitatively the same biochemical and toxic effects as TCDD.ED50Median effect dose, i.e. the dose that produces a defined effect in 50%ERODEthoxyresorufin

-O-deethylase. This enzyme is used as a biomarker forIn vitroIn vivoLD50Median lethal dose, i.e. the dose that kills 50% of the test population.LOEL (LOAEL)Lowest observed (adverse) effect level.NOEL (NOAEL)No observed (adverse) effect level.PCBPolychlorinated biphenyl.PCDDPolychlorinated dibenzo-PCDFPolychlorinated dibenzofuran.SevesoAccident in 1976 in Italy where people were exposed to TCDD.TCDD2,3,7,8-tetrachlorodibenzo-TEFToxic equivalency facto

r, relative toxicity of an individual congener toTEQToxic Equivalent, the sum of concentrations of dioxin-like compoundstimes their individual TEF measured in a sample, representing theTDITolerable Daily Intake, a limit below which humans are consideredprotected from toxic effects.YuchengA mass outbreak of food poisoning in Taiwan in 1979 followingYushoA mass outbreak of food poisoning in Japan in 1968 following Task 8 - Human toxicology AEA Technolo

gyPage A13 of 17 The following documents were consulted in the course of this study:ToxicCrit RevToxicolexpression outside GST-P positive foci in liver of rats was associated to the tumour promotionEnviron Toxicol Pharmacol Task 8 - Human toxicology AEA TechnologyPage A14 of 17 PJJ, Seegal RF, Smits-van Prooije AE, Touwen BCL, Weisglas-Kuperus N, Winneke GToxicol Ind Healthpreneoplastic liver cells in the rat. cells. Environ Toxicol PharmacolToxicolo

gy Toxicologist Task 8 - Human toxicology AEA TechnologyPage A15 of 17 Task 8 - Human toxicology AEA TechnologyPage A16 of 17 Toxicol ApplToxicolLettSurvey: Evaluation of the H-4-II E bioassay for screening environmental samples for dioxin-Pharmacol ToxicolAnn Rev Pharmacol ToxicolToxicologychildren. Task 8 - Human toxicology AEA TechnologyPage A17 of 17 Kociba RJ, Keyes DG, Beyer JE, Carreon RM, Wade CE, Dittenber D, Kalnins R, Frauson L,Toxicol Ap

plinfants' mental and psychomotor development. Arch Toxicol-dioxin-mediated increases in cellCancerTCDD in laboratory animals: Implications for risk assessment. Toxicol Ind HealthLancet Task 8 - Human toxicology AEA TechnologyPage A18 of 17 CRC Critical Reviews in BiochemistryOkey AB, Riddick DS, Harper PA (1994) The Ah receptor: Mediator of the toxicity ofToxicol LettCrit Rev Toxicolnitrosamine. receptor. In: Inducible gene expression, Baeuerle PA (

ed), Birkh?user, Boston, pp 177-205.in laboratory animals: Effects, mechanisms and animal models. Toxicolhairless mice. Macaca mulattacontaminants in Taiwan. Task 8 - Human toxicology AEA TechnologyPage A19 of 17 Crit Rev ToxicolEnviron Toxicol Chemtreated intact but not ovarieectomized rats. Cancer Lett-dioxin in female Task 8 - Human toxicology AEA TechnologyPage A20 of 17 Waern F, Flodström S, Busk L, Kronevi T, Nordgren I, Ahlborg UG (1991) Rel