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Event: 360

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Decrease, Population growth rate

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Decrease, Population growth rate
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Population

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
population growth rate population of organisms decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Androgen receptor agonism leading to reproductive dysfunction AdverseOutcome Dan Villeneuve (send email) Open for citation & comment WPHA/WNT Endorsed
Aromatase inhibition leading to reproductive dysfunction AdverseOutcome Dan Villeneuve (send email) Open for citation & comment WPHA/WNT Endorsed
Estrogen receptor agonism leading to reproductive dysfunction AdverseOutcome Tom Hutchinson (send email) Under Development: Contributions and Comments Welcome
Estrogen receptor antagonism leading to reproductive dysfunction AdverseOutcome Dan Villeneuve (send email) Open for citation & comment EAGMST Under Review
Cyclooxygenase inhibition 2 AdverseOutcome Dalma Martinovic-Weigelt (send email) Under Development: Contributions and Comments Welcome
Prolyl hydroxylase inhibition AdverseOutcome Dalma Martinovic-Weigelt (send email) Under Development: Contributions and Comments Welcome
Unknown MIE leading to reprodl AdverseOutcome Dalma Martinovic-Weigelt (send email) Under Development: Contributions and Comments Welcome
DIO2i posterior swim bladder AdverseOutcome Dries Knapen (send email) Under Development: Contributions and Comments Welcome EAGMST Approved
DIO2i anterior swim bladder AdverseOutcome Dries Knapen (send email) Under Development: Contributions and Comments Welcome EAGMST Approved
DIO1i posterior swim bladder AdverseOutcome Dries Knapen (send email) Under Development: Contributions and Comments Welcome EAGMST Approved
DIO1i anterior swim bladder AdverseOutcome Dries Knapen (send email) Under Development: Contributions and Comments Welcome EAGMST Approved
TPOi anterior swim bladder AdverseOutcome Dries Knapen (send email) Under Development: Contributions and Comments Welcome EAGMST Approved
Cyclooxygenase inhibition 3 AdverseOutcome Dalma Martinovic-Weigelt (send email) Under Development: Contributions and Comments Welcome
Cyclooxygenase inhibition 4 AdverseOutcome Dalma Martinovic-Weigelt (send email) Under Development: Contributions and Comments Welcome
Cyclooxygenase inhibition 1 AdverseOutcome Dalma Martinovic-Weigelt (send email) Under Development: Contributions and Comments Welcome
Cyclooxygenase inhibition 5 AdverseOutcome Dalma Martinovic-Weigelt (send email) Under Development: Contributions and Comments Welcome
tyrosinase, fish AdverseOutcome Young Jun Kim (send email) Open for citation & comment Under Development
AHR mediated epigenetic reproductive failure AdverseOutcome Jon Doering (send email) Under development: Not open for comment. Do not cite
AChE inhibition - acute mortality AdverseOutcome Dan Villeneuve (send email) Under Development: Contributions and Comments Welcome Under Development
AChE inhibition - acute mortality via predation AdverseOutcome Kristie Sullivan (send email) Under development: Not open for comment. Do not cite
GR Agonism Leading to Impaired Fin Regeneration AdverseOutcome Alexander Cole (send email) Open for citation & comment
DNMT inhibtion leading to population decline (1) AdverseOutcome You Song (send email) Under Development: Contributions and Comments Welcome
DNMT inhibtion leading to population decline (2) AdverseOutcome You Song (send email) Under Development: Contributions and Comments Welcome
DNMT inhibtion leading to population decline (3) AdverseOutcome You Song (send email) Under Development: Contributions and Comments Welcome
DNMT inhibtion leading to population decline (4) AdverseOutcome You Song (send email) Under Development: Contributions and Comments Welcome
DNMT inhibtion leading to transgenerational effects (1) AdverseOutcome You Song (send email) Under Development: Contributions and Comments Welcome
DNMT inhibtion leading to transgenerational effects (2) AdverseOutcome You Song (send email) Under Development: Contributions and Comments Welcome
5α-reductase,female fish AdverseOutcome Young Jun Kim (send email) Open for citation & comment Under Development
retinaldehyde dehydrogenase inhibition,population decline AdverseOutcome Young Jun Kim (send email) Under Development: Contributions and Comments Welcome Under Development
Aromatase inhibition leads to male-biased sex ratio via impacts on gonad differentiation AdverseOutcome Kelvin Santana Rodriguez (send email) Under Development: Contributions and Comments Welcome
Thermal stress leading to population decline (3) AdverseOutcome You Song (send email) Under development: Not open for comment. Do not cite
Thermal stress leading to population decline (2) AdverseOutcome You Song (send email) Under development: Not open for comment. Do not cite
Thermal stress leading to population decline (1) AdverseOutcome You Song (send email) Under development: Not open for comment. Do not cite
TPOi retinal layer structure AdverseOutcome Lucia Vergauwen (send email) Open for citation & comment EAGMST Under Review
11β-hydroxylase inhibition, infertility in fish AdverseOutcome Young Jun Kim (send email) Under development: Not open for comment. Do not cite Under Development
11βHSD inhibition, decreased population trajectory AdverseOutcome Young Jun Kim (send email) Under development: Not open for comment. Do not cite Under Development
AR agonism leading to male-biased sex ratio AdverseOutcome Dan Villeneuve (send email) Open for citation & comment
ROS production leading to population decline via photosynthesis inhibition AdverseOutcome Knut Erik Tollefsen (send email) Under development: Not open for comment. Do not cite
ROS production leading to population decline via mitochondrial dysfunction AdverseOutcome Knut Erik Tollefsen (send email) Under development: Not open for comment. Do not cite
DNA damage leading to population decline via programmed cell death AdverseOutcome Knut Erik Tollefsen (send email) Under development: Not open for comment. Do not cite
OEC damage leading to population decline via photosynthesis inhibition AdverseOutcome Knut Erik Tollefsen (send email) Under development: Not open for comment. Do not cite
TPOi eye size AdverseOutcome Lucia Vergauwen (send email) Under development: Not open for comment. Do not cite Under Development
TPOi photoreceptor patterning AdverseOutcome Lucia Vergauwen (send email) Under development: Not open for comment. Do not cite Under Development
Inhibition of Fyna leading to increased mortality AdverseOutcome Vid Modic (send email) Open for citation & comment
GSK3beta inactivation leads to increased mortality AdverseOutcome Vid Modic (send email) Open for citation & comment
Deposition of energy leading to population decline via DSB and follicular atresia AdverseOutcome Knut Erik Tollefsen (send email) Under development: Not open for comment. Do not cite
Deposition of energy leading to population decline via DSB and apoptosis AdverseOutcome Knut Erik Tollefsen (send email) Under development: Not open for comment. Do not cite
Energy deposition leading to population decline via DNA oxidation and follicular atresia AdverseOutcome You Song (send email) Under development: Not open for comment. Do not cite
Energy deposition leading to population decline via DNA oxidation and oocyte apoptosis AdverseOutcome You Song (send email) Under development: Not open for comment. Do not cite
Deposition of energy leads to reduced cocoon hatchability AdverseOutcome Deborah Oughton (send email) Under development: Not open for comment. Do not cite
OAT1 inhibition AdverseOutcome Kellie Fay (send email) Under Development: Contributions and Comments Welcome
Cox1 inhibition renal failure AdverseOutcome Kellie Fay (send email) Under Development: Contributions and Comments Welcome
5-HTT block to population decline AdverseOutcome Kellie Fay (send email) Under Development: Contributions and Comments Welcome
5-HTT leading to population decline AdverseOutcome Kellie Fay (send email) Under Development: Contributions and Comments Welcome
Inhibition of CYP7B leads to decreased locomotor activity AdverseOutcome Florence Pagé-Larivière (send email) Not under active development
Inhibition of CYP7B activity leads to decreased sexual behavior AdverseOutcome Florence Pagé-Larivière (send email) Not under active development
PPARa Agonism Impairs Fish Reproduction AdverseOutcome Ashley Kittelson (send email) Open for citation & comment

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
all species all species High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages Not Specified

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific Not Specified

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

A population can be defined as a group of interbreeding organisms, all of the same species, occupying a specific space during a specific time (Vandermeer and Goldberg 2003, Gotelli 2008).  As the population is the biological level of organization that is often the focus of ecological risk assessments, population growth rate (and hence population size over time) is important to consider within the context of applied conservation practices.

If N is the size of the population and t is time, then the population growth rate (dN/dt) is proportional to the instantaneous rate of increase, r, which measures the per capita rate of population increase over a short time interval. Therefore, r, is a difference between the instantaneous birth rate (number of births per individual per unit of time; b) and the instantaneous death rate (number of deaths per individual per unit of time; d) [Equation 1]. Because  r is an instantaneous rate, its units can be changed via division.  For example, as there are 24 hours in a day, an r of 24 individuals/(individual x day) is equal to an r of 1 individual/(individual/hour) (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020). 

Equation 1:  r = b - d

This key event refers to scenarios where r < 0 (instantaneous death rate exceeds instantaneous birth rate).

Examining r in the context of population growth rate:

● A population will decrease to extinction when the instantaneous death rate exceeds the instantaneous birth rate (r < 0).  

           ● The smaller the value of r below 1, the faster the population will decrease to zero.  

● A population will increase when resources are available and the instantaneous birth rate exceeds the instantaneous death rate (r > 0)

           ● The larger the value that r exceeds 1, the faster the population can increase over time      

● A population will neither increase or decrease when the population growth rate equals 0 (either due to N = 0, or if the per capita birth and death rates are exactly balanced).  For example, the per capita birth and death rates could become exactly balanced due to density dependence and/or to the effect of a stressor that reduces survival and/or reproduction (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020).     

Effects incurred on a population from a chemical or non-chemical stressor could have an impact directly upon birth rate (reproduction) and/or death rate (survival), thereby causing a decline in population growth rate.  

● Example of direct effect on r:  Exposure to 17b-trenbolone reduced reproduction (i.e., reduced b) in the fathead minnow over 21 days at water concentrations ranging from 0.0015 to about 41 mg/L (Ankley et al. 2001; Miller and Ankley 2004).             

Alternatively, a stressor could indirectly impact survival and/or reproduction.  

● Example of indirect effect on r:  Exposure of non-sexually differentiated early life stage fathead minnow to the fungicide prochloraz has been shown to produce male-biased sex ratios based on gonad differentiation, and resulted in projected change in population growth rate (decrease in reproduction due to a decrease in females and thus recruitment) using a population model. (Holbech et al., 2012; Miller et al. 2022)

Density dependence can be an important consideration:

● The effect of density dependence depends upon the quantity of resources present within a landscape.  A change in available resources could increase or decrease the effect of density dependence and therefore cause a change in population growth rate via indirectly impacting survival and/or reproduction.  

● This concept could be thought of in terms of community level interactions whereby one species is not impacted but a competitor species is impacted by a chemical stressor resulting in a greater availability of resources for the unimpacted species.  In this scenario, the impacted species would experience a decline in population growth rate. The unimpacted species would experience an increase in population growth rate (due to a smaller density dependent effect upon population growth rate for that species).       

Closed versus open systems:

● The above discussion relates to closed systems (there is no movement of individuals between population sites) and thus a declining population growth rate cannot be augmented by immigration.  

● When individuals depart (emigrate out of a population) the loss will diminish population growth rate.  

Population growth rate applies to all organisms, both sexes, and all life stages.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Population growth rate (instantaneous growth rate) can be measured by sampling a population over an interval of time (i.e. from time t = 0 to time t = 1).  The interval of time should be selected to correspond to the life history of the species of interest (i.e. will be different for rapidly growing versus slow growing populations). The population growth rate, r, can be determined by taking the difference (subtracting) between the initial population size, Nt=0 (population size at time t=0), and the population size at the end of the interval, Nt=1 (population size at time t = 1), and then subsequently dividing by the initial population size. 

Equation 2:  r = (Nt=1 - Nt=0) / Nt=0

The diversity of forms, sizes, and life histories among species has led to the development of a vast number of field techniques for estimation of population size and thus population growth over time (Bookhout 1994, McComb et al. 2021).  

● For stationary species an observational strategy may involve dividing a habitat into units. After setting up the units, samples are performed throughout the habitat at a select number of units (determined using a statistical sampling design) over a time interval (at time t = 0 and again at time t = 1), and the total number of organisms within each unit are counted. The numbers recorded are assumed to be representative for the habitat overall, and can be used to estimate the population growth rate within the entire habitat over the time interval.  

● For species that are mobile throughout a large range, a strategy such as using a mark-recapture method may be employed (i.e. tags, bands, transmitters) to determine a count over a time interval (at time = 0 and again at time =1).   

Population growth rate can also be estimated using mathematical model constructs (for example, ranging from simple differential equations to complex age or stage structured matrix projection models and individual based modeling approaches), and may assume a linear or nonlinear population increase over time (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020). The AOP framework can be used to support the translation of pathway-specific mechanistic data into responses relevant to population models and output from the population models, such as changing (declining) population growth rate, can be used to assess and manage risks of chemicals (Kramer et al. 2011). As such, this translational capability can increase the capacity and efficiency of safety assessments both for single chemicals and chemical mixtures (Kramer et al. 2011).  

Some examples of modeling constructs used to investigate population growth rate:

● A modeling construct could be based upon laboratory toxicity tests to determine effect(s) that are then linked to the population model and used to estimate decline in population growth rate.  Miller et al. (2007) used concentration–response data from short term reproductive assays with fathead minnow (Pimephales promelas) exposed to endocrine disrupting chemicals in combination with a population model to examine projected alterations in population growth rate.  

● A model construct could be based upon a combination of effects-based monitoring at field sites (informed by an AOP) and a population model.  Miller et al. (2015) applied a population model informed by an AOP to project declines in population growth rate for white suckers (Catostomus commersoni) using observed changes in sex steroid synthesis in fish exposed to a complex pulp and paper mill effluent in Jackfish Bay, Ontario, Canada. Furthermore, a model construct could be comprised of a series of quantitative models using KERs that culminates in the estimation of change (decline) in population growth rate.  

● A quantitative adverse outcome pathway (qAOP) has been defined as a mathematical construct that models the dose–response or response–response relationships of all KERs described in an AOP (Conolly et al. 2017, Perkins et al. 2019). Conolly et al. (2017) developed a qAOP using data generated with the aromatase inhibitor fadrozole as a stressor and then used it to predict potential population‐level impacts (including decline in population growth rate). The qAOP modeled aromatase inhibition (the molecular initiating event) leading to reproductive dysfunction in fathead minnow (Pimephales promelas) using 3 computational models: a hypothalamus–pituitary–gonadal axis model (based on ordinary differential equations) of aromatase inhibition leading to decreased vitellogenin production (Cheng et al. 2016), a stochastic model of oocyte growth dynamics relating vitellogenin levels to clutch size and spawning intervals (Watanabe et al. 2016), and a population model (Miller et al. 2007).

● Dynamic energy budget (DEB) models offer a methodology that reverse engineers stressor effects on growth, reproduction, and/or survival into modular characterizations related to the acquisition and processing of energy resources (Nisbet et al. 2000, Nisbet et al. 2011).  Murphy et al. (2018) developed a conceptual model to link DEB and AOP models by interpreting AOP key events as measures of damage-inducing processes affecting DEB variables and rates.

● Endogenous Lifecycle Models (ELMs), capture the endogenous lifecycle processes of growth, development, survival, and reproduction and integrate these to estimate and predict expected fitness (Etterson and Ankley, 2021).  AOPs can be used to inform ELMs of effects of chemical stressors on the vital rates that determine fitness, and to decide what hierarchical models of endogenous systems should be included within an ELM (Etterson and Ankley, 2021).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Consideration of population size and changes in population size over time is potentially relevant to all living organisms.

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Maintenance of sustainable fish and wildlife populations (i.e., adequate to ensure long-term delivery of valued ecosystem services) is a widely accepted regulatory goal upon which risk assessments and risk management decisions are based.

References

List of the literature that was cited for this KE description. More help
  • Ankley GT, Jensen KM, Makynen EA, Kahl MD, Korte JJ, Hornung MW, Henry TR, Denny JS, Leino RL, Wilson VS, Cardon MD, Hartig PC, Gray LE. 2003. Effects of the androgenic growth promoter 17b-trenbolone on fecundity and reproductive endocrinology of the fathead minnow. Environ. Toxicol. Chem. 22: 1350–1360.
  • Bookhout TA. 1994. Research and management techniques for wildlife and habitats. The Wildlife Society, Bethesda, Maryland. 740 pp.
  • Caswell H. 2001. Matrix Population Models. Sinauer Associates, Inc., Sunderland, MA, USA
  • Cheng WY, Zhang Q, Schroeder A, Villeneuve DL, Ankley GT, Conolly R.  2016.  Computational modeling of plasma vitellogenin alterations in response to aromatase inhibition in fathead minnows. Toxicol Sci 154: 78–89.
  • Conolly RB, Ankley GT, Cheng W-Y, Mayo ML, Miller DH, Perkins EJ, Villeneuve DL, Watanabe KH. 2017. Quantitative adverse outcome pathways and their application to predictive toxicology. Environ. Sci. Technol. 51:  4661-4672.
  • Etterson MA, Ankley GT.  2021.  Endogenous Lifecycle Models for Chemical Risk Assessment. Environ. Sci. Technol. 55:  15596-15608. 
  • Gotelli NJ, 2008. A Primer of Ecology. Sinauer Associates, Inc., Sunderland, MA, USA.
  • Holbech H, Kinnberg KL, Brande-Lavridsen N, Bjerregaard P, Petersen GI, Norrgren L, Orn S, Braunbeck T, Baumann L, Bomke C, Dorgerloh M, Bruns E, Ruehl-Fehlert C, Green JW, Springer TA, Gourmelon A. 2012 Comparison of zebrafish (Danio rerio) and fathead minnow (Pimephales promelas) as test species in the Fish Sexual Development Test (FSDT). Comp. Biochem. Physiol. C Toxicol. Pharmacol. 155:  407–415.
  • Kramer VJ, Etterson MA, Hecker M, Murphy CA, Roesijadi G, Spade DJ, Stromberg JA, Wang M, Ankley GT.  2011.  Adverse outcome pathways and risk assessment: Bridging to population level effects.  Environ. Toxicol. Chem. 30, 64-76.
  • McComb B, Zuckerberg B, Vesely D, Jordan C.  2021.  Monitoring Animal Populations and their Habitats: A Practitioner's Guide.  Pressbooks, Oregon State University, Corvallis, OR Version 1.13, 296 pp. 
  • Miller DH, Villeneuve DL, Santana Rodriguez KG, Ankley GT. 2022.  A multidimensional matrix model for predicting the effect of male biased sex ratios on fish populations. Environmental Toxicology and Chemistry 41(4): 1066-1077.
  • Miller DH, Tietge JE, McMaster ME, Munkittrick KR, Xia X, Griesmer DA, Ankley GT. 2015. Linking mechanistic toxicology to population models in forecasting recovery from chemical stress: A case study from Jackfish Bay, Ontario, Canada. Environmental Toxicology and Chemistry 34(7):  1623-1633.
  • Miller DH, Jensen KM, Villeneuve DE, Kahl MD, Makynen EA, Durhan EJ, Ankley GT. 2007. Linkage of biochemical responses to population-level effects: A case study with vitellogenin in the fathead minnow (Pimephales promelas). Environ Toxicol Chem 26:  521–527.
  • Miller DH, Ankley GT. 2004. Modeling impacts on populations: Fathead minnow (Pimephales promelas) exposure to the endocrine disruptor 17b-trenbolone as a case study. Ecotox Environ Saf 59: 1–9.
  • Murphy CA, Nisbet RM, Antczak P, Garcia-Reyero N, Gergs A, Lika K, Mathews T, Muller EB, Nacci D, Peace A, Remien CH, Schultz IR, Stevenson LM, Watanabe KH.  2018.  Incorporating suborganismal processes into dynamic energy budget models for ecological risk assessment.  Integrated Environmental Assessment and Management 14(5):  615–624.
  • Murray DL, Sandercock BK (editors).  2020.  Population ecology in practice.  Wiley-Blackwell, Oxford UK, 448 pp.
  • Nisbet RM, Jusup M, Klanjscek T, Pecquerie L.  2011.  Integrating dynamic energy budget (DEB) theory with traditional bioenergetic models.  The Journal of Experimental Biology 215: 892-902.
  • Nisbet RM, Muller EB, Lika K, Kooijman SALM. 2000. From molecules to ecosystems through dynamic energy budgets. J Anim Ecol 69:  913–926.
  • Perkins EJ,  Ashauer R, Burgoon L, Conolly R, Landesmann B,, Mackay C, Murphy CA, Pollesch N, Wheeler JR, Zupanic A, Scholzk S.  2019.  Building and applying quantitative adverse outcome pathway models for chemical hazard and risk assessment.  Environmental Toxicology and Chemistry 38(9): 1850–1865. 
  • Vandermeer JH, Goldberg DE. 2003.  Population ecology: first principles.  Princeton University Press, Princeton NJ, 304 pp.
  • Villeneuve DL, Crump D, Garcia-Reyero N, Hecker M, Hutchinson TH, LaLone CA, Landesmann B, Lattieri T, Munn S, Nepelska M, Ottinger MA, Vergauwen L, Whelan M. Adverse outcome pathway (AOP) development 1: Strategies and principles. Toxicol Sci. 2014: 142:312–320
  • Watanabe KH, Mayo M, Jensen KM, Villeneuve DL, Ankley GT, Perkins EJ.  2016.  Predicting fecundity of fathead minnows (Pimephales promelas) exposed to endocrine‐disrupting chemicals using a MATLAB(R)‐based model of oocyte growth dynamics. PLoS One 11:  e0146594.