A Simple Toxicokinetic Model Exhibiting Complex Dynamics and Nonlinear Exposure Response
Uncertainty in model predictions of exposure response at low exposures is a problem for risk assessment. A particular interest is the internal concentration of an agent in biological systems as a function of external exposure concentrations. Physiologically based pharmacokinetic (PBPK) models permit...
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| Veröffentlicht in: | Risk analysis 2020-12, Vol.40 (12), p.2561-2571 |
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| container_title | Risk analysis |
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| creator | Park, Robert M. |
| description | Uncertainty in model predictions of exposure response at low exposures is a problem for risk assessment. A particular interest is the internal concentration of an agent in biological systems as a function of external exposure concentrations. Physiologically based pharmacokinetic (PBPK) models permit estimation of internal exposure concentrations in target tissues but most assume that model parameters are either fixed or instantaneously dose‐dependent. Taking into account response times for biological regulatory mechanisms introduces new dynamic behaviors that have implications for low‐dose exposure response in chronic exposure. A simple one‐compartment simulation model is described in which internal concentrations summed over time exhibit significant nonlinearity and nonmonotonicity in relation to external concentrations due to delayed up‐ or downregulation of a metabolic pathway. These behaviors could be the mechanistic basis for homeostasis and for some apparent hormetic effects. |
| doi_str_mv | 10.1111/risa.13547 |
| format | Article |
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These behaviors could be the mechanistic basis for homeostasis and for some apparent hormetic effects.</description><identifier>ISSN: 0272-4332</identifier><identifier>EISSN: 1539-6924</identifier><identifier>DOI: 10.1111/risa.13547</identifier><identifier>PMID: 32632964</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>Chronic exposure ; Delayed ; Dose response ; Exposure ; Homeostasis ; hormesis ; Metabolic pathways ; Nonlinear dynamics ; Nonlinear response ; Nonlinear systems ; Nonlinearity ; PBPK ; Pharmacokinetics ; Reaction time ; Regulatory mechanisms (biology) ; Risk assessment ; Simulation ; Uncertainty ; upregulation</subject><ispartof>Risk analysis, 2020-12, Vol.40 (12), p.2561-2571</ispartof><rights>2020 Society for Risk Analysis</rights><rights>2020 Society for Risk Analysis.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4487-64804c37a46673bbe085dcc08527186a8f735005d3314cade43d52211d4163b53</citedby><cites>FETCH-LOGICAL-c4487-64804c37a46673bbe085dcc08527186a8f735005d3314cade43d52211d4163b53</cites><orcidid>0000-0001-5849-8292</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Frisa.13547$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Frisa.13547$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32632964$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Park, Robert M.</creatorcontrib><title>A Simple Toxicokinetic Model Exhibiting Complex Dynamics and Nonlinear Exposure Response</title><title>Risk analysis</title><addtitle>Risk Anal</addtitle><description>Uncertainty in model predictions of exposure response at low exposures is a problem for risk assessment. 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These behaviors could be the mechanistic basis for homeostasis and for some apparent hormetic effects.</description><subject>Chronic exposure</subject><subject>Delayed</subject><subject>Dose response</subject><subject>Exposure</subject><subject>Homeostasis</subject><subject>hormesis</subject><subject>Metabolic pathways</subject><subject>Nonlinear dynamics</subject><subject>Nonlinear response</subject><subject>Nonlinear systems</subject><subject>Nonlinearity</subject><subject>PBPK</subject><subject>Pharmacokinetics</subject><subject>Reaction time</subject><subject>Regulatory mechanisms (biology)</subject><subject>Risk assessment</subject><subject>Simulation</subject><subject>Uncertainty</subject><subject>upregulation</subject><issn>0272-4332</issn><issn>1539-6924</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kctOGzEYRq2qqAmXDQ-ALHVTIQ34NvbMBikKtCCFInGR2FkejwMOM_bUztDk7esQiIBFvbAXPj7_Z30A7GN0hNM6DjaqI0xzJr6AIc5pmfGSsK9giIggGaOUDMB2jDOEMEK5-AYGlHBKSs6G4H4Eb2zbNQbe-oXV_sk6M7caXvraNPBs8WgrO7fuAY79ilrA06VTrdURKlfD39416YEKiex87IOB1yZ23kWzC7amqolm7_XcAXc_z27H59nk6tfFeDTJNGOFyDgrENNUKMa5oFVlUJHXWqedCFxwVUwFzVPqmlLMtKoNo3VOCMY1w5xWOd0BJ2tv11etqbVx86Aa2QXbqrCUXln58cbZR_ngn6UQrChLlAQ_XgXB_-lNnMvWRm2aRjnj-ygJS9OQEJwm9PsndOb74NL3EiVQwVleiEQdrikdfIzBTDdhMJKrwuSqMPlSWIIP3sffoG8NJQCvgb-2Mcv_qOT1xc1oLf0HMF-gRw</recordid><startdate>202012</startdate><enddate>202012</enddate><creator>Park, Robert M.</creator><general>Blackwell Publishing Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7ST</scope><scope>7U7</scope><scope>7U9</scope><scope>8BJ</scope><scope>8FD</scope><scope>C1K</scope><scope>FQK</scope><scope>FR3</scope><scope>H94</scope><scope>JBE</scope><scope>JQ2</scope><scope>KR7</scope><scope>M7N</scope><scope>SOI</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5849-8292</orcidid></search><sort><creationdate>202012</creationdate><title>A Simple Toxicokinetic Model Exhibiting Complex Dynamics and Nonlinear Exposure Response</title><author>Park, Robert M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4487-64804c37a46673bbe085dcc08527186a8f735005d3314cade43d52211d4163b53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Chronic exposure</topic><topic>Delayed</topic><topic>Dose response</topic><topic>Exposure</topic><topic>Homeostasis</topic><topic>hormesis</topic><topic>Metabolic pathways</topic><topic>Nonlinear dynamics</topic><topic>Nonlinear response</topic><topic>Nonlinear systems</topic><topic>Nonlinearity</topic><topic>PBPK</topic><topic>Pharmacokinetics</topic><topic>Reaction time</topic><topic>Regulatory mechanisms (biology)</topic><topic>Risk assessment</topic><topic>Simulation</topic><topic>Uncertainty</topic><topic>upregulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Park, Robert M.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Environment Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>International Bibliography of the Social Sciences (IBSS)</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>International Bibliography of the Social Sciences</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>International Bibliography of the Social Sciences</collection><collection>ProQuest Computer Science Collection</collection><collection>Civil Engineering Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Environment Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Risk analysis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Park, Robert M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Simple Toxicokinetic Model Exhibiting Complex Dynamics and Nonlinear Exposure Response</atitle><jtitle>Risk analysis</jtitle><addtitle>Risk Anal</addtitle><date>2020-12</date><risdate>2020</risdate><volume>40</volume><issue>12</issue><spage>2561</spage><epage>2571</epage><pages>2561-2571</pages><issn>0272-4332</issn><eissn>1539-6924</eissn><abstract>Uncertainty in model predictions of exposure response at low exposures is a problem for risk assessment. A particular interest is the internal concentration of an agent in biological systems as a function of external exposure concentrations. Physiologically based pharmacokinetic (PBPK) models permit estimation of internal exposure concentrations in target tissues but most assume that model parameters are either fixed or instantaneously dose‐dependent. Taking into account response times for biological regulatory mechanisms introduces new dynamic behaviors that have implications for low‐dose exposure response in chronic exposure. A simple one‐compartment simulation model is described in which internal concentrations summed over time exhibit significant nonlinearity and nonmonotonicity in relation to external concentrations due to delayed up‐ or downregulation of a metabolic pathway. These behaviors could be the mechanistic basis for homeostasis and for some apparent hormetic effects.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>32632964</pmid><doi>10.1111/risa.13547</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-5849-8292</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0272-4332 |
| ispartof | Risk analysis, 2020-12, Vol.40 (12), p.2561-2571 |
| issn | 0272-4332 1539-6924 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7748990 |
| source | Business Source Complete; Wiley Online Library All Journals |
| subjects | Chronic exposure Delayed Dose response Exposure Homeostasis hormesis Metabolic pathways Nonlinear dynamics Nonlinear response Nonlinear systems Nonlinearity PBPK Pharmacokinetics Reaction time Regulatory mechanisms (biology) Risk assessment Simulation Uncertainty upregulation |
| title | A Simple Toxicokinetic Model Exhibiting Complex Dynamics and Nonlinear Exposure Response |
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