Uncertainties Associated with Assessing the Risk of an Endocrine Active Substance in the Canadian Environment

2001 ◽  
Vol 36 (2) ◽  
pp. 319-330 ◽  
Author(s):  
Mark Servos ◽  
Don Bennie ◽  
Kent Burnison ◽  
Philippa Cureton ◽  
Nicol Davidson ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Endocrine Disruption ◽  
Endocrine System ◽  
Problem Formulation ◽  
Normal Function ◽  
Weight Of Evidence ◽  
Biological Responses ◽  
Low Concentrations ◽  
Multigenerational Effects

Abstract A number of biological responses and multigenerational effects, mediated through the disruption of endocrine systems, have been observed in biota exposed to relatively low concentrations of environmental contaminants. These types of responses need to be considered within a weight of evidence approach in our risk assessment and risk management frameworks. However, including endocrine responses in an environmental risk assessment introduces a number of uncertainties that must be considered. A risk assessment of nonylphenol and nonylphenol polyethoxylates (NP/NPE) is used as a case study to demonstrate the sources and magnitude of some of the uncertainties associated with using endocrine disruption as an assessment endpoint. Even with this relatively well studied group of substances, there are substantial knowledge gaps which contribute to the overall uncertainties, limiting the interpretation within the risk assessment. The uncertainty of extrapolating from in vitro or biochemical responses to higher levels of organization or across species is not well understood. The endocrine system is very complex and chemicals can interact or interfere with the normal function of endocrine systems in a number of ways (e.g., receptors, hormones) which may or may not result in an adverse responses in the whole organism. Using endocrine responses can lead to different conclusions than traditional endpoints due to a variety of factors, such as differences in relative potencies of chemicals for specific endpoints (e.g., receptor binding versus chronic toxicity). The uncertainties can also be considerably larger and the desirability of using endocrine endpoints should be carefully evaluated. Endocrine disruption is a mode of action and not a functional endpoint and this needs to be considered carefully in the problem formulation stage and the interpretation of the weight of evidence.

scholarly journals Adverse Outcome Pathway Development for Assessment of Lung Carcinogenicity by Nanoparticles

2021 ◽  
Vol 3 ◽  
Author(s):  
Penny Nymark ◽  
Hanna L. Karlsson ◽  
Sabina Halappanavar ◽  
Ulla Vogel
Keyword(s):  
Lung Cancer ◽  
Risk Assessment ◽  
Adverse Outcome ◽  
Animal Experiments ◽  
Engineered Nanoparticles ◽  
Alternative Methods ◽  
Weight Of Evidence ◽  
Adverse Outcome Pathway ◽  
Alternative Mechanism

Lung cancer, one of the most common and deadly forms of cancer, is in some cases associated with exposure to certain types of particles. With the rise of nanotechnology, there is concern that some engineered nanoparticles may be among such particles. In the absence of epidemiological evidence, assessment of nanoparticle carcinogenicity is currently performed on a time-consuming case-by-case basis, relying mainly on animal experiments. Non-animal alternatives exist, including a few validated cell-based methods accepted for regulatory risk assessment of nanoparticles. Furthermore, new approach methodologies (NAMs), focused on carcinogenic mechanisms and capable of handling the increasing numbers of nanoparticles, have been developed. However, such alternative methods are mainly applied as weight-of-evidence linked to generally required animal data, since challenges remain regarding interpretation of the results. These challenges may be more easily overcome by the novel Adverse Outcome Pathway (AOP) framework, which provides a basis for validation and uptake of alternative mechanism-focused methods in risk assessment. Here, we propose an AOP for lung cancer induced by nanosized foreign matter, anchored to a selection of 18 standardized methods and NAMs for in silico- and in vitro-based integrated assessment of lung carcinogenicity. The potential for further refinement of the AOP and its components is discussed in relation to available nanosafety knowledge and data. Overall, this perspective provides a basis for development of AOP-aligned alternative methods-based integrated testing strategies for assessment of nanoparticle-induced lung cancer.

scholarly journals Recent Purification Technologies and Human Health Risk Assessment of Microplastics

Materials ◽  
2020 ◽  
Vol 13 (22) ◽  
pp. 5196
Author(s):  
Jun Woo Park ◽  
Su Jin Lee ◽  
Dae Youn Hwang ◽  
Sungbaek Seo
Keyword(s):  
Risk Assessment ◽  
Health Risk ◽  
Food Chain ◽  
Human Health Risk ◽  
Endocrine System ◽  
Biological Degradation ◽  
Human Beings ◽  
Identification Methods

Microplastic (MP)-based contaminants in the environment are pervasive, but standard technologies used for MP identification have not yet been reported. Human beings take up MPs from the environmental ecosystem through the food chain without any particular purification. MPs can penetrate into capillaries from the bloodstream, resulting in endocrine system disorders or toxicity. In this review, we introduced several technologies, such as filtration using membranes, biological degradation, electrocoagulation, and removal using nanoparticles, used for the purification of MPs or related contaminants. Current studies of identification methods of MPs and evaluation tests of MPs exposure-based harmfulness in vitro and in vivo were summarized.

Endocrine disruption and the USFDA's Center for Drug Evaluation and Research

2003 ◽  
Vol 75 (11-12) ◽  
pp. 2605-2607
Author(s):  
A. Jacobs ◽  
Paul Brown ◽  
James Farrelly ◽  
J. E. Fisher ◽  
D. Morse
Keyword(s):  
Risk Management ◽  
Endocrine Disruption ◽  
Drug Evaluation ◽  
Developmental Toxicity ◽  
Clinical Decision ◽  
Weight Of Evidence ◽  
Endocrine Effects ◽  
Reproductive Effects

Drugs may have intended or unintended endocrine effects. Drug evaluation may include both in vitro and in vivo evaluations of toxicity and developmental/reproductive effects. After a signal is identified, human relevance is of utmost concern. An integration "tool" that formalizes a weight-of-evidence approach has been developed to assess concern about reproductive/ developmental toxicity to humans. This approach can be used to assess concern about an endocrine disruption signal. A signal alone does not mean a concern for humans. An effect needs to have biologic relevance, and exposure thresholds for effects may exist. Risk/benefit for a particular drug is a clinical decision and may vary by the drug indication. Risk management for an identified concern could include wording in patient communications, tracking distribution or limited distribution, and patient or pregnancy registries.

Integrated Decision-tree Testing Strategies for Developmental and Reproductive Toxicity with Respect to the Requirements of the EU REACH Legislation

2008 ◽  
Vol 36 (1) ◽  
pp. 65-80 ◽  
Author(s):  
Christina Grindon ◽  
Robert Combes ◽  
Mark T.D. Cronin ◽  
David W. Roberts ◽  
John F. Garrod
Keyword(s):  
Risk Assessment ◽  
Decision Tree ◽  
Endocrine Disruption ◽  
Reproductive Toxicity ◽  
Toxicity Testing ◽  
Alternative Methods ◽  
The European Union ◽  
Animal Testing ◽  
Testing Strategies

Liverpool John Moores University and FRAME conducted a research project, sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with the REACH system. This paper focuses on the prospects for the use of alternative methods (both in vitro and in silico) in developmental and reproductive toxicity testing. It considers many tests based on primary cells and cell lines, and the available expert systems and QSARs for developmental and reproductive toxicity, and also covers tests for endocrine disruption. Ways in which reduction and refinement measures can be used are also discussed, particularly the use of an enhanced one-generation reproductive study, which could potentially replace the two-generation study, and therefore considerably reduce the number of animals required in reproductive toxicity. Decision-tree style integrated testing strategies are also proposed for developmental and reproductive toxicity and for endocrine disruption, followed by a number of recommendations for the future facilitation of developmental and reproductive toxicity testing, with respect to human risk assessment.

scholarly journals Highlighting the gaps in hazard and risk assessment of unregulated Endocrine Active Substances in surface waters: retinoids as a European case study

2021 ◽  
Vol 33 (1) ◽  
Author(s):  
Barbara Kubickova ◽  
Carmel Ramwell ◽  
Klara Hilscherova ◽  
Miriam Naomi Jacobs
Keyword(s):  
Risk Assessment ◽  
Surface Waters ◽  
Endocrine System ◽  
Signalling Pathway ◽  
Weight Of Evidence ◽  
Signalling Pathways ◽  
Hazard And Risk ◽  
Hazard And Risk Assessment ◽  
Active Substances

AbstractRegulatory hazard and risk assessment of endocrine-active substances currently specifies four modes of action: interference with sex hormone (oestrogen, androgen) pathways, steroidogenesis, and thyroid hormone signalling. This does not encompass the full complexity of the endocrine system and its extended interfaces with environmental pollutants that can potentially disrupt the carefully maintained balance. Here we take the retinoid signalling pathway as a European case study for both, under- and unregulated endocrine pathways and outline the different levels of interference, discuss their adversity, and indicate crosstalk to other signalling pathways. Retinoid compounds already exist in drinking water sources, occur naturally in cyanobacterial blooms and/or enter surface waters via wastewater discharge, where they pose a potential hazard to the environment and human health - a situation that can be expected to worsen due to water shortages induced by climate-change and population growth. We briefly review relevant aspects of current endocrine disruptor (ED) testing for regulatory purposes and then expand upon the needs for inclusion of disruption of retinoid signalling in (ED) regulatory safety assessment contributing to adverse health outcomes that include cognitive function and neurological disease. An overview of developmental effects of retinoid signalling disruption across species highlights critical processes and potential crosstalk with other signalling pathways. A focused weight of evidence-based evaluation of the biologically plausible associations between neurological disorders and altered retinoid signalling highlights the evidence gaps. We show that monitoring only a limited number of anthropogenic priority chemicals in water is insufficient to address the environmental risks of retinoid signalling disruption. To comprehensively assess impacts on the endpoints, processes, and pathways of the endocrine system that are most vulnerable to chemical interference we need further investigation of the true mixture composition in environmental matrices. On a weight of evidence-basis this information can then be integrated into a reliable, inclusive, quantitative approach that ultimately accommodates all the critical pathways. By focusing on the retinoid signalling pathway, we intend to improve the scope and relevance of an integrated approach for the risk assessment of endocrine disruptors.

A Weight-of-Evidence Approach for Assessing Interactions in Chemical Mixtures

1992 ◽  
Vol 8 (6) ◽  
pp. 377-406 ◽  
Author(s):  
M. M. Mumtaz ◽  
P. R. Durkin
Keyword(s):  
Risk Assessment ◽  
Scientific Evidence ◽  
Assessment Process ◽  
Risk Assessments ◽  
Weight Of Evidence ◽  
Interaction Patterns ◽  
Chemical Mixtures ◽  
Qualitative Risk Assessment

The risk assessment process must encompass all available toxicological data and scientific evidence on the plausible toxicities of a chemical or chemical mixture. As an extension to the approaches used to conduct risk assessments on chemical mixtures, a preliminary scheme, analogous to the IARC classification of carcinogens, is proposed to express the weight of evidence for the interactions in binary mixtures. This scheme is based on composite representation of all the toxicological evidence from animal bioassays and human data, pharmacokinetics studies, metabolism studies, and structure activity relationships. In addition, factors such as the relevance of route, duration and sequence of exposure, toxicological significance of interactions and the quality of in vivo and in vitro data are taken into consideration. The scheme yields an alphanumeric classification that can be used for qualitative risk assessment, and has the potential, as demonstrated in this paper, for quantitative application to site-specific risk assessments. Furthermore, the scheme can be used to estimate interactions or form hypotheses concerning binary interactions. It is flexible and allows all pertinent information to be incorporated in a methodical and consistent manner. Research is needed to identify interaction patterns for simultaneous and sequential exposure scenarios of chemical pollutants in order that this scheme may be developed further and its usefulness and limitations may be tested.

Integrated Decision-tree Testing Strategies for Developmental and Reproductive Toxicity with Respect to the Requirements of the EU REACH Legislation

2008 ◽  
Vol 36 (1_suppl) ◽  
pp. 123-138 ◽  
Author(s):  
Christina Grindon ◽  
Robert Combes ◽  
Mark T.D. Cronin ◽  
David W. Roberts ◽  
John F. Garrod
Keyword(s):  
Risk Assessment ◽  
Decision Tree ◽  
Endocrine Disruption ◽  
Reproductive Toxicity ◽  
Toxicity Testing ◽  
Alternative Methods ◽  
The European Union ◽  
Animal Testing ◽  
Testing Strategies

Liverpool John Moores University and FRAME conducted a research project, sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with the REACH system. This paper focuses on the prospects for the use of alternative methods (both in vitro and in silico) in developmental and reproductive toxicity testing. It considers many tests based on primary cells and cell lines, and the available expert systems and QSARs for developmental and reproductive toxicity, and also covers tests for endocrine disruption. Ways in which reduction and refinement measures can be used are also discussed, particularly the use of an enhanced one-generation reproductive study, which could potentially replace the two-generation study, and therefore considerably reduce the number of animals required in reproductive toxicity. Decision-tree style integrated testing strategies are also proposed for developmental and reproductive toxicity and for endocrine disruption, followed by a number of recommendations for the future facilitation of developmental and reproductive toxicity testing, with respect to human risk assessment.

Bioanalytical methodologies for clinical investigation of endocrine-disrupting chemicals: a comprehensive update

Bioanalysis ◽  
2021 ◽  
Author(s):  
Rajesh Pradhan ◽  
Siddhanth Hejmady ◽  
Rajeev Taliyan ◽  
Gautam Singhvi ◽  
Rajesh Khadgawat ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Human Health ◽  
Clinical Investigation ◽  
Endocrine Disrupting Chemicals ◽  
Endocrine System ◽  
Detection Methods ◽  
Low Doses ◽  
In Vitro Bioassay ◽  
Endocrine Disrupting

Endocrine-disrupting chemicals (EDCs) are xenobiotics that disrupt the endocrine system in humans at ecologically significant concentrations. Various substances are exposed to human health via routes including food, water, air and skin that result in disastrous maladies at low doses as well. Therefore EDCs need a meticulous strategy of analysis for dependable and consistent monitoring in humans. The management and risk assessment necessitate advancements in the detection methodologies of EDCs. Hyphenated MS-based chromatograph and other validated laboratory analysis methods are widely available and employed. Besides, in vitro bioassay techniques and biosensors are also used to conduct accurate toxicological tests. This article provides a revision of various bioanalytical detection methods and technologies for the clinical estimation of EDCs.

Kinetics of Various 99mTc-Sn-Pyrophosphate Compounds in the Rat

1977 ◽  
Vol 16 (04) ◽  
pp. 157-162 ◽  
Author(s):  
C. Schümichen ◽  
B. Mackenbrock ◽  
G. Hoffmann
Keyword(s):  
Normal Saline ◽  
Half Life ◽  
Compound A ◽  
Short Half Life ◽  
Low Concentrations ◽  
The Stability ◽  
Kinetics Of ◽  
In Vitro Stability

SummaryThe bone-seeking 99mTc-Sn-pyrophosphate compound (compound A) was diluted both in vitro and in vivo and proved to be unstable both in vitro and in vivo. However, stability was much better in vivo than in vitro and thus the in vitro stability of compound A after dilution in various mediums could be followed up by a consecutive evaluation of the in vivo distribution in the rat. After dilution in neutral normal saline compound A is metastable and after a short half-life it is transformed into the other 99mTc-Sn-pyrophosphate compound A is metastable and after a short half-life in bone but in the kidneys. After dilution in normal saline of low pH and in buffering solutions the stability of compound A is increased. In human plasma compound A is relatively stable but not in plasma water. When compound B is formed in a buffering solution, uptake in the kidneys and excretion in urine is lowered and blood concentration increased.It is assumed that the association of protons to compound A will increase its stability at low concentrations while that to compound B will lead to a strong protein bond in plasma. It is concluded that compound A will not be stable in vivo because of a lack of stability in the extravascular space, and that the protein bond in plasma will be a measure of its in vivo stability.

In Vitro Effects of Ethanol on Rabbit Platelet Aggregation, Secretion of Granule Contents, and Cyclic AMP Levels in the Presence of Prostacyclin

1989 ◽  
Vol 61 (02) ◽  
pp. 254-258 ◽  
Author(s):  
Margaret L Rand ◽  
Peter L Gross ◽  
Donna M Jakowec ◽  
Marian A Packham ◽  
J Fraser Mustard
Keyword(s):  
Cyclic Amp ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Inhibitory Effects ◽  
Low Concentrations ◽  
Rabbit Platelets ◽  
High Concentrations ◽  
In Vitro Effects ◽  
Aggregation Of Platelets

SummaryEthanol, at physiologically tolerable concentrations, inhibits platelet responses to low concentrations of collagen or thrombin, but does not inhibit responses of washed rabbit platelets stimulated with high concentrations of ADP, collagen, or thrombin. However, when platelet responses to high concentrations of collagen or thrombin had been partially inhibited by prostacyclin (PGI2), ethanol had additional inhibitory effects on aggregation and secretion. These effects were also observed with aspirin- treated platelets stimulated with thrombin. Ethanol had no further inhibitory effect on aggregation of platelets stimulated with ADP, or the combination of ADP and epinephrine. Thus, the inhibitory effects of ethanol on platelet responses in the presence of PGI2 were very similar to its inhibitory effects in the absence of PGI2, when platelets were stimulated with lower concentrations of collagen or thrombin. Ethanol did not appear to exert its inhibitory effects by increasing cyclic AMP above basal levels and the additional inhibitory effects of ethanol in the presence of PGI2 did not appear to be brought about by further increases in platelet cyclic AMP levels.

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