Table 3.

Major categories of “potentially relevant” supplemental material.

Category	Description
In vitro, ex vivo, or in silico “mechanistic” studies	In vitro, ex vivo, or in silico studies reporting measurements related to a health outcome that inform the biological or chemical events associated with phenotypic effects, in both mammalian and nonmammalian model systems.
Absorption, Distribution, Metabolism, and Excretion (ADME)	ADME studies are primarily controlled experiments where defined exposures usually occur by intravenous, oral, inhalation, or dermal routes, and the concentration of particles, a chemical, or its metabolites in blood or serum, other body tissues, or excreta are then measured. These data are used to estimate the amount absorbed (A), distributed to different organs (D), metabolized (M), and/or excreted/eliminated (E) through urine, breath, feces, etc. ADME data can also be collected from human subjects who have had environmental or workplace exposures that are not quantified or fully defined. However, to be useful, such data must involve either repeated measurements over a time period when exposure is known (e.g., is zero because previous exposure ended) or time- and subject-matched tissue or excreta concentrations (e.g., plasma and urine, or maternal and cord blood). ADME data, especially metabolism and tissue partition coefficient information, can be generated using in vitro model systems. Although in vitro data may not be as definitive as in vivo data, these studies should also be tracked as ADME. For large evidence bases it may be appropriate to separately track the in vitro ADME studies. Note: Studies describing environmental fate and transport or metabolism in bacteria are not tagged as ADME.
Classical Pharmacokinetic (PK) Model Studies, or Physiologically based Pharmacokinetic (PBPK) Model studies	Classical Pharmacokinetic (PK) or Dosimetry Model Studies: Classical PK or dosimetry modeling usually divides the body into just one or two compartments, which are not specified by physiology, where movement of a chemical into, between, and out of the compartments is quantified empirically by fitting model parameters to ADME data. Physiologically based Pharmacokinetic (PBPK) or Mechanistic Dosimetry Model Studies: PBPK models represent the body as various compartments (e.g., liver, lung, slowly perfused tissue, richly perfused tissue) to quantify the movement of chemicals or particles into and out of the body (compartments) by defined routes of exposure, metabolism, and elimination, and thereby estimate concentrations in blood or target tissues.
Nonmammalian model systems	Studies in nonmammalian model systems, e.g., Xenopus, fish, birds, C. elegans.
Transgenic mammalian model systems	Transgenic studies in mammalian model systems.
Non-oral or noninhalation routes of administration	Studies in which humans or animals (whole organism) were exposed via a non-oral or noninhalation route (e.g., injection, dermal exposure).
Exposure characteristics (no health outcome assessment)	Exposure characteristic studies which include data that are unrelated to health outcomes but which provide information on exposure sources or measurement properties of the environmental agent (e.g., demonstrate a biomarker of exposure).
Mixture studies	Mixture studies that are not considered PECO-relevant because they do not contain an exposure or treatment group assessing only the chemical of interest. This category is generally used for experimental studies and generally does not apply to epidemiological studies where the exposure source may be unclear.
Case reports	Case reports describing health outcomes after exposure will be tracked as potentially relevant supplemental information when the number of subjects is three or fewer.
Records with no original data	Records that do not contain original data, such as other agency assessments, informative scientific literature reviews, editorials, or commentaries.
Conference abstracts	Records that do not contain sufficient documentation to support study evaluation and data extraction.
European Chemicals Agency (ECHA) read-across	Data on a non-relevant chemical that makes inferences about a relevant PFAS chemical.
Presumed duplicate	Duplicate studies (e.g., published vs. unpublished reports) identified during data extraction and study quality evaluation.

Note: “Potentially relevant” supplemental material are studies that do not meet the PECO criteria but may still contain information of interest that was tracked during screening. Additionally, the definitions in the table follow standard template language that is used in systematic evidence maps developed by the U.S. EPA^22,51 and have only been adjusted, where appropriate, for the specific needs of this SEM. PECO, populations, exposures, comparators, and outcomes; PFAS, PFAS per- and polyfluoroalkyl substances.