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Article ; Online: Invited Perspective: How Relevant Are Mode-of-Action Considerations for the Assessment and Prediction of Mixture Effects?

Kortenkamp, Andreas

2022 Volume 130, Issue 4, Page(s) 41302

Language	English
Publishing date	2022-04-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	195189-0
ISSN	1552-9924 ; 0091-6765 ; 1078-0475
ISSN (online)	1552-9924
ISSN	0091-6765 ; 1078-0475
DOI	10.1289/EHP11051
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Book ; Conference proceedings: Endocrine disruptors

Kortenkamp, Andreas

exposure assessment, novel end points, and low-dose and mixture effects ; synthesis of papers presented at the Prague workshop focusing on novel research data and new thoughts and approaches on the ecological relevance of endocrine disruption in wildlife

(Environmental health perspectives ; 115, Suppl. 1)

2007

Series title	Environmental health perspectives ; 115, Suppl. 1
Collection
Language	English
Size	136 S. : Ill., graph. Darst.
Publisher	National Inst. of Health, National Inst. of Environmental Health Sciences
Publishing place	Research Triangle Park, NC
Publishing country	United States
Document type	Book ; Conference proceedings
HBZ-ID	HT015429175
Database	Catalogue ZB MED Medicine, Health

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Zs B 1360 -115,Suppl.1-	verfügbar in Königswinter	Königswinter

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Article: Disruption of the thyroid hormone system and patterns of altered thyroid hormones after gestational chemical exposures in rodents - a systematic review.

Forner-Piquer, Isabel / Baig, Asma H / Kortenkamp, Andreas

Frontiers in endocrinology

2024 Volume 14, Page(s) 1323284

Abstract: We present a comprehensive overview of changes in thyroxine (T4) and thyroid stimulating hormone (TSH) serum concentrations after pre-gestational, gestational and/or lactation exposures of rodents to various chemicals that affect the thyroid hormone ... ...

Abstract	We present a comprehensive overview of changes in thyroxine (T4) and thyroid stimulating hormone (TSH) serum concentrations after pre-gestational, gestational and/or lactation exposures of rodents to various chemicals that affect the thyroid hormone system. We show that T4 and TSH changes consistent with the idealized view of the hypothalamic-pituitary-thyroid (HPT) feedback loop (T4 decrements accompanied by TSH increases) are observed with only a relatively small set of chemicals. Most substances affect concentrations of various thyroid hormones without increasing TSH. Studies of altered T4 concentrations after gestational exposures are limited to a relatively small set of chemicals in which pesticides, pharmaceuticals and industrial chemicals are under-represented. Our risk-of-bias analysis exposed deficits in T4/TSH analytics as a problem area. By relating patterns of T4 - TSH changes to mode-of-action (MOA) information, we found that chemicals capable of disrupting the HPT feedback frequently affected thyroid hormone synthesis, while substances that produced T4 serum decrements without accompanying TSH increases lacked this ability, but often induced liver enzyme systems responsible for the elimination of TH by glucuronidation. Importantly, a multitude of MOA leads to decrements of serum T4. The current EU approaches for identifying thyroid hormone system-disrupting chemicals, with their reliance on altered TH serum levels as indicators of a hormonal mode of action and thyroid histopathological changes as indicators of adversity, will miss chemicals that produce T4/T3 serum decreases without accompanying TSH increases. This is of concern as it may lead to a disregard for chemicals that produce developmental neurotoxicity by disrupting adequate T4/T3 supply to the brain, but without increasing TSH.
MeSH term(s)	Animals ; Female ; Rodentia ; Thyroid Hormones ; Thyroxine ; Thyroid Gland ; Thyrotropin
Chemical Substances	Thyroid Hormones ; Thyroxine (Q51BO43MG4) ; Thyrotropin (9002-71-5)
Language	English
Publishing date	2024-01-30
Publishing country	Switzerland
Document type	Systematic Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1323284
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Article ; Online: Which chemicals should be grouped together for mixture risk assessments of male reproductive disorders?

Kortenkamp, Andreas

Molecular and cellular endocrinology

2019 Volume 499, Page(s) 110581

Abstract: There is concern about cumulative exposures to compounds that disrupt male sexual differentiation in foetal life, leading to irreversible effects in adulthood, including declines in semen quality, testes non-descent, malformations of the penis and testis ...

Abstract	There is concern about cumulative exposures to compounds that disrupt male sexual differentiation in foetal life, leading to irreversible effects in adulthood, including declines in semen quality, testes non-descent, malformations of the penis and testis cancer. Traditional chemical-by-chemical risk assessment approaches cannot capture the likely cumulative health risks. Past efforts of focusing on combinations of phthalates, a subgroup of chemicals suspected of contributing to these risks, do not go far enough, as they ignore the contribution of other types of chemicals. With the aim of providing criteria for the inclusion of additional chemicals in mixture risks assessments for male reproductive health, this paper examines the mechanisms of action of various chemicals capable of disrupting male sexual differentiation. An Adverse Outcome Pathway (AOP) network for malformations of the male reproductive system is constructed that includes new findings about the role of disruptions of prostaglandin signalling. This network is used to identify pathways that converge at critical nodal points to produce down-stream adverse effects. From this knowledge, combinations of chemicals with different mechanisms of action are predicted that should result in cumulative effects. These predictions are then mapped against evidence from experimental mixture studies with relevant combinations. From the outcome of this analysis it is concluded that cumulative assessment groups for male reproductive health risks should not only include phthalates but also comprise androgen receptor (AR) antagonists, chemicals capable of disrupting steroid synthesis, InsL3 production, prostaglandin signalling and co-planar polychlorinated dibenzo-dioxins together with other dioxin-like compounds. This list goes far beyond what has been suggested previously. A minimum set of chemicals to be assessed together with phthalates includes pesticides such as vinclozolin, prochloraz, procymidone, linuron, the pain killers paracetamol, aspirin and ibuprofen, pharmaceuticals such as finasteride, ketoconazole, and the lipid-lowering drug simvastin, poly-chlorinated dibenzo-dioxins and other dioxin-like pollutants and phenolics such as bisphenol A and butylparaben. AOP network analyses are essential to overcome difficulties in establishing groupings of chemicals for mixture risk assessments that derive from a narrow focus on mechanisms and modes of action.
MeSH term(s)	Adverse Outcome Pathways ; Androgen Receptor Antagonists/adverse effects ; Genitalia, Male/drug effects ; Humans ; Male ; Models, Biological ; Pesticides/adverse effects ; Phthalic Acids/adverse effects ; Risk Assessment/methods
Chemical Substances	Androgen Receptor Antagonists ; Pesticides ; Phthalic Acids
Language	English
Publishing date	2019-09-13
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2019.110581
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Article ; Online: Cadmium exposures and deteriorations of cognitive abilities: estimation of a reference dose for mixture risk assessments based on a systematic review and confidence rating.

Chatterjee, Mousumi / Kortenkamp, Andreas

Environmental health : a global access science source

2022 Volume 21, Issue 1, Page(s) 69

Abstract: To support a mixture risk assessment with a focus on developmental neurotoxicity we evaluated the strength of evidence for associations of cadmium exposures with declines in IQ by conducting a systematic review and confidence rating. We searched peer- ... ...

Abstract	To support a mixture risk assessment with a focus on developmental neurotoxicity we evaluated the strength of evidence for associations of cadmium exposures with declines in IQ by conducting a systematic review and confidence rating. We searched peer-reviewed studies published in English between 2012 and July 2021 and identified 15 eligible studies (11 prospective cohort studies, and 4 cross-sectional studies). Of the 10 studies that observed associations of cadmium exposure with child IQ declines, two achieved an overall "High (H)" confidence rating, five a "Medium to High (M/H)", one a "Medium (M)" and two a "Low (L)" confidence rating. Five studies did not detect significant associations between cadmium exposure and reduced cognitive ability; of these, two received a "High (H)" confidence rating, two an overall rating of "Medium to High (M/H)" and one a "Medium (M)" rating. The null findings reported by the "High (H)" and Medium to High (M/H)" studies could partly be explained by low exposures to cadmium or confounding with high levels of lead. By using a one-compartment toxicokinetic model in a reverse dosimetry approach, we estimated that a daily intake of 0.2 μg/kg body weight/day corresponds to urinary cadmium levels no longer associated with cognitive declines observed in a "High (H)"-confidence study. This estimate is 1.8-fold lower than the current health-based guidance value (HBGV) for kidney toxicity of 0.36 μg/kg bodyweight/day established by the European Food Safety Authority (EFSA). Our value does not have the normative character associated with health-based guidance values and is intended only as a reasonable estimate for the purpose of mixture risk assessments. However, with cadmium exposures in Europe between 0.28 (middle bound) and up to 0.52 μg/kg bodyweight/day (95
MeSH term(s)	Cadmium/toxicity ; Cadmium/urine ; Child ; Cognition ; Cross-Sectional Studies ; Female ; Humans ; Pregnancy ; Prospective Studies ; Risk Assessment
Chemical Substances	Cadmium (00BH33GNGH)
Language	English
Publishing date	2022-07-14
Publishing country	England
Document type	Journal Article ; Review ; Systematic Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2092232-2
ISSN	1476-069X ; 1476-069X
ISSN (online)	1476-069X
ISSN	1476-069X
DOI	10.1186/s12940-022-00881-9
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Article ; Online: Declining semen quality and polybrominated diphenyl ethers (PBDEs): Review of the literature to support the derivation of a reference dose for a mixture risk assessment.

Ermler, Sibylle / Kortenkamp, Andreas

International journal of hygiene and environmental health

2022 Volume 242, Page(s) 113953

Abstract: To support a mixture risk assessment for chemicals that interfere with male reproductive health, we reviewed the literature to identify studies of polybrominated diphenyl ethers (PBDEs) and poor semen quality. Several epidemiological studies have shown ... ...

Abstract	To support a mixture risk assessment for chemicals that interfere with male reproductive health, we reviewed the literature to identify studies of polybrominated diphenyl ethers (PBDEs) and poor semen quality. Several epidemiological studies have shown associations of PBDE exposures with declining semen quality, non-descending testes and penile malformations. In rodent studies, poor semen quality, changes in testosterone levels and reproductive tissues have been observed. In vitro studies with reporter gene constructs show PBDE congeners as androgen receptor antagonists, and mixture studies in these systems have demonstrated that PBDE congeners act together with other androgen receptor antagonists. These observations led us to attempt the estimation of reference doses for specific PBDE congeners that can be used in a future mixture risk assessment for deteriorations of semen quality. While epidemiological studies provide support for such associations, they were uninformative for derivations of reference doses, due to the incompatibility of dose metrics used in exposure assessments. We therefore based our estimates on animal studies. Using a rigorous confidence rating approach, we found robust evidence that BDE-47 produced reductions in semen quality. We identified only one high confidence study of BDE-99 and accordingly evaluated the strength of evidence as moderate. One high confidence, and several medium confidence experimental studies observed declines in semen quality after BDE-209 exposure. Using established risk assessment procedures, we estimated that BDE-47 exposures below 0.15 μg/kg/d are unlikely to lead to reductions in semen quality. The corresponding exposures for BDE-99 and BDE-209 are 0.003 μg/kg/d and 1000 μg/kg/d. It is planned to use these estimates as reference doses in a mixture risk assessment of deteriorations in semen quality, involving multiple other chemicals also contributing to poor semen quality.
MeSH term(s)	Androgen Receptor Antagonists ; Animals ; Halogenated Diphenyl Ethers ; Male ; Polybrominated Biphenyls ; Risk Assessment ; Semen Analysis
Chemical Substances	Androgen Receptor Antagonists ; Halogenated Diphenyl Ethers ; Polybrominated Biphenyls
Language	English
Publishing date	2022-03-22
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2009176-X
ISSN	1618-131X ; 1438-4639
ISSN (online)	1618-131X
ISSN	1438-4639
DOI	10.1016/j.ijheh.2022.113953
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Article ; Online: Systematic review of associations of polychlorinated biphenyl (PCB) exposure with declining semen quality in support of the derivation of reference doses for mixture risk assessments.

Ermler, Sibylle / Kortenkamp, Andreas

Environmental health : a global access science source

2022 Volume 21, Issue 1, Page(s) 94

Abstract: Background: Mixture risk assessments require reference doses for common health endpoints of all the chemicals to be considered together. In support of a mixture risk assessment for male reproductive health, we conducted a systematic review of the ... ...

Abstract	Background: Mixture risk assessments require reference doses for common health endpoints of all the chemicals to be considered together. In support of a mixture risk assessment for male reproductive health, we conducted a systematic review of the literature on associations between exposures to Polychlorinated Biphenyls (PCBs) and declines in semen quality. PCBs can act as Aryl-hydrocarbon Receptor (AhR)-agonists and Androgen Receptor (AR)-antagonists, both mechanisms which can affect sperm parameters. PCBs and other AR-antagonists can produce additive combination effects. Based on these observations our objective was to systematically gather data from animal and human studies to derive a reference dose for declines in semen quality for individual PCB. Methods: We systematically reviewed and evaluated the evidence in human epidemiological and experimental animal studies on associations between PCBs and deteriorations in semen quality. Human data and findings from animal studies with PCB mixtures were considered as supporting evidence. Information for individual congeners from animal studies was required for inclusion in mixture risk assessment. Using a robust confidence rating approach, we identified suitable studies to derive reference doses for individual PCB congeners. Results: Evaluation of human epidemiological studies revealed several reports of adverse effects on sperm parameters linked to PCB exposures, although some studies reported improved semen quality. Our review of experimental animal studies found that treatments with PCBs affected semen quality, in most cases adversely. We found robust evidence that PCB-118 and -169 were linked to declines in semen quality. Evidence for adverse effects of PCB-126, -132, -149, and -153 was moderate, whereas for PCB-77 it was slight and for PCB-180 indeterminate. Using widely accepted risk assessment procedures, we estimated reference dose values of 0.0029 µg/kg/day for PCB-118 and 0.00533 µg/kg/day for PCB-169. In addition, we derived values for PCB-126: 0.000073 µg/kg/day, PCB-132: 0.0228 µg/kg/day, PCB-149: 0.656 µg/kg/day, and PCB-153: 0.0058 µg/kg/day. Conclusions: We found robust evidence for links between PCB exposure and deteriorations in semen quality, and derived reference doses for a set of congeners. We intend to use these values in combination with congener-specific exposure data in a mixture risk assessment for declines in semen quality, involving several other antiandrogenic chemicals.
MeSH term(s)	Animals ; Humans ; Male ; Polychlorinated Biphenyls/toxicity ; Receptors, Androgen ; Risk Assessment ; Semen ; Semen Analysis
Chemical Substances	Receptors, Androgen ; 2,3',4,4',5-pentachlorobiphenyl (2B2AQE8U50) ; Polychlorinated Biphenyls (DFC2HB4I0K) ; 3,4,5,3',4'-pentachlorobiphenyl (TSH69IA9XF)
Language	English
Publishing date	2022-10-11
Publishing country	England
Document type	Journal Article ; Systematic Review
ZDB-ID	2092232-2
ISSN	1476-069X ; 1476-069X
ISSN (online)	1476-069X
ISSN	1476-069X
DOI	10.1186/s12940-022-00904-5
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Article ; Online: Drivers of divergent assessments of bisphenol-A hazards to semen quality by various European agencies, regulators and scientists.

Kortenkamp, Andreas / Martin, Olwenn / Iacovidou, Eleni / Scholze, Martin

International journal of hygiene and environmental health

2023 Volume 255, Page(s) 114293

Abstract: The downward revision of the bisphenol A (BPA) Health-based Guidance Value (HBGV) by the European Food Safety Authority (EFSA) has led to disagreements with other regulatory agencies, among them the German Federal Institute for Risk Assessment (BfR). The ...

Abstract	The downward revision of the bisphenol A (BPA) Health-based Guidance Value (HBGV) by the European Food Safety Authority (EFSA) has led to disagreements with other regulatory agencies, among them the German Federal Institute for Risk Assessment (BfR). The BfR has recently published an alternative Tolerable Daily Intake (TDI), 1000-times higher than the EFSA HBGV of 0.2 ng/kg/d. While the EFSA value is defined in relation to immunotoxicity, the BfR alternative TDI is based on declines in sperm counts resulting from exposures in adulthood. Earlier, we had used semen quality deteriorations to estimate a BPA Reference Dose (RfD) of 3 ng/kg/d for use in mixture risk assessments of male reproductive health. We derived this estimate from animal studies of gestational BPA exposures which both EFSA and BfR viewed as irrelevant for human hazard characterisations. Here, we identify factors that drive these diverging views. We find that the fragmented, endpoint-oriented study evaluation system used by EFSA and BfR, with its emphasis on data that can support dose-response analyses, has obscured the overall BPA effect pattern relevant to male reproductive effects. This has led to a disregard for the effects of gestational BPA exposures. We also identify problems with the study evaluation schemes used by EFSA and BfR which leads to the omission of entire streams of evidence from consideration. The main driver of the diverging views of EFSA and BfR is the refusal by BfR to accept immunotoxic effects as the basis for establishing an HBGV. We find that switching from immunotoxicity to declines in semen quality as the basis for deriving a BPA TDI by deterministic or probabilistic approaches produces values in the range of 2.4-6.6 ng/kg/d, closer to the present EFSA HBGV of 0.2 ng/kg/d than the BfR TDI of 200 ng/kg/d. The proposed alternative BfR value is the result of value judgements which erred on the side of disregarding evidence that could have supported a lower TDI. The choices made in terms of selecting key studies and methods for dose-response analyses produced a TDI that comes close to doses shown to produce effects on semen quality in animal studies and in human studies of adult BPA exposures.
MeSH term(s)	Adult ; Animals ; Male ; Humans ; Semen Analysis ; Semen ; Phenols/toxicity ; Benzhydryl Compounds/toxicity
Chemical Substances	bisphenol A (MLT3645I99) ; Phenols ; Benzhydryl Compounds
Language	English
Publishing date	2023-11-15
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2009176-X
ISSN	1618-131X ; 1438-4639
ISSN (online)	1618-131X
ISSN	1438-4639
DOI	10.1016/j.ijheh.2023.114293
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Article ; Online: Endocrine disruptors: The burden of endocrine-disrupting chemicals in the USA.

Kortenkamp, Andreas

Nature reviews. Endocrinology

2016 Volume 13, Issue 1, Page(s) 6–7

Language	English
Publishing date	2016-12-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2489381-X
ISSN	1759-5037 ; 1759-5029
ISSN (online)	1759-5037
ISSN	1759-5029
DOI	10.1038/nrendo.2016.198
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Article: Which chemicals should be grouped together for mixture risk assessments of male reproductive disorders?

Kortenkamp, Andreas

Molecular and cellular endocrinology. 2019 Sept. 12,

2019

Abstract	There is concern about cumulative exposures to compounds that disrupt male sexual differentiation in foetal life, leading to irreversible effects in adulthood, including declines in semen quality, testes non-descent, malformations of the penis and testis cancer. Traditional chemical-by-chemical risk assessment approaches cannot capture the likely cumulative health risks. Past efforts of focusing on combinations of phthalates, a subgroup of chemicals suspected of contributing to these risks, do not go far enough, as they ignore the contribution of other types of chemicals. With the aim of providing criteria for the inclusion of additional chemicals in mixture risks assessments for male reproductive health, this paper examines the mechanisms of action of various chemicals capable of disrupting male sexual differentiation. An Adverse Outcome Pathway (AOP) network for malformations of the male reproductive system is constructed that includes new findings about the role of disruptions of prostaglandin signalling. This network is used to identify pathways that converge at critical nodal points to produce down-stream adverse effects. From this knowledge, combinations of chemicals with different mechanisms of action are predicted that should result in cumulative effects. These predictions are then mapped against evidence from experimental mixture studies with relevant combinations. From the outcome of this analysis it is concluded that cumulative assessment groups for male reproductive health risks should not only include phthalates but also comprise androgen receptor (AR) antagonists, chemicals capable of disrupting steroid synthesis, InsL3 production, prostaglandin signalling and co-planar polychlorinated dibenzo-dioxins together with other dioxin-like compounds. This list goes far beyond what has been suggested previously. A minimum set of chemicals to be assessed together with phthalates includes pesticides such as vinclozolin, prochloraz, procymidone, linuron, the pain killers paracetamol, aspirin and ibuprofen, pharmaceuticals such as finasteride, ketoconazole, and the lipid-lowering drug simvastin, poly-chlorinated dibenzo-dioxins and other dioxin-like pollutants and phenolics such as bisphenol A and butylparaben. AOP network analyses are essential to overcome difficulties in establishing groupings of chemicals for mixture risk assessments that derive from a narrow focus on mechanisms and modes of action.
Keywords	abnormal development ; acetaminophen ; adulthood ; adverse effects ; adverse outcome pathways ; androgen receptors ; antagonists ; aspirin ; bisphenol A ; ibuprofen ; ketoconazole ; linuron ; males ; mechanism of action ; neoplasms ; penis ; phthalates ; pollutants ; polychlorinated dibenzodioxins ; prediction ; prochloraz ; procymidone ; prostaglandins ; reproductive disorders ; risk ; risk assessment process ; semen quality ; sexual development ; testes ; vinclozolin
Language	English
Dates of publication	2019-0912
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2019.110581
Database	NAL-Catalogue (AGRICOLA)

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