Much of the data used in assessing DART concerns for workers come from toxicity tests conducted in laboratory animals (usually rats and mice) rather than studies in humans. Although inhalation is the major route of entry for hazardous chemicals in the work environment, many animal studies are conducted using oral dosing. As a result, route-to-route extrapolation is a common practice in OEL derivation. Studies in other species (fish, insects, birds) may also be available for particular compounds; however, these studies are generally not used to establish safe human exposure levels due to the greater degree of inter-species differences and the lack of standardized testing protocols. While data from studies of exposed workers are obviously highly relevant to the occupational setting, these studies are typically limited in number and are often complicated by factors such as simultaneous exposures to multiple chemicals. Understanding of DART risks for any given chemical generally requires multiple animal studies, which can be expensive and time-consuming. For these reasons, adequate DART data are lacking for most chemicals. The biology of human reproductive and developmental processes is complex. development involves rapid division and differentiation to transform a single stem cell into the billions of highly specialized cells of the newborn infant. This process is under very tight biological control, with the timing of cell division, migration, and specialization governed by a specific set of genes. These genes are turned on and off during pregnancy, directing the development of different fetal tissues. As a result, there are well-recognized “windows of susceptibility” where fetal development may be disrupted by chemical exposure. For example, formation of many fetal organs occurs between the third and eighth week of pregnancy. It is thus important to encourage employees to inform health and safety personnel of their pregnancy (or their intended pregnancy) as early as possible, or, better, to maintain exposures for women and men below appropriately considered OELs at all times. Historically, the scientific rationales for setting OELs were limited and aimed at minimizing or preventing significant acute toxicity. Thus, most early OELs did not include consideration of potential DART effects. Today, DART studies (if available) are commonly considered when selecting the critical effect from which to base derivation of an OEL. Agents that cause DART effects in the absence of other types of systemic health effects are considered to be selectively toxic to reproduction and development. Conversely, agents that cause DART effects only at or above doses or concentrations that cause other systemic effects in the adult may be doing so indirectly (that is, the DART effects may be secondary to parental effects). Thus, when DART effects are appropriately considered, the resulting OEL will be based either on protection of a DART effect or on a more or equally sensitive non-DART effect (which will also be protective of DART effects). A third scenario, one that indirectly considers DART effects, employs an assessment factor for database uncertainty during development of an OEL. Used when sufficient data to assess the potential for DART (or other) effects are lacking, this process results in lowering the OEL to account for missing data that might have identified a DART effect as a more sensitive endpoint. The level of documentation and transparency in setting OELs varies widely by organization. Many of the leading organizations provide concise documentation of the underlying studies and rationale for their OELs, which often includes a section on DART effects. The basis for some ACGIH Threshold Limit Values (TLVs) is exclusively, or in part, DART effects (for example, 2-ethoxyethanol, methyl isopropyl ketone, toluene). Many of the German Maximale Arbeitsplatz-Konzentrations (MAK) recommendations explicitly address the potential for DART effects via a “MAK Pregnancy Risk Group Classification” (see Table 1). MAKs assigned to Group A or B are clearly not intended to be protective of DART effects, but those in Group C are. We have found that documentation of the consideration of DART effects in setting OELs, including the uncertainty therein, is not as robust as that of some environmental exposure criteria, such as reference concentrations (RfCs) established by EPA and Minimal Risk Levels (MRLs) established by ATSDR. The overall trend, however, in setting OELs is toward increased documentation. This trend will better serve stakeholders in assessing whether OELs are protective of DART effects.

Readers are encouraged to review the December 2015 supplement of the , a special issue on OELs. Other sources of information in this article include:

ACGIH: (2015).

Deutsche Forschungsgemeinschaft (DFG): (September 2015).

EPA: “TSCA Work Plan Chemical Risk Assessment: Trichloroethylene: Degreasing, Spot Cleaning and Arts & Crafts Uses (CASRN 79-01-6)” ().

Lewandowski, TA: “Developmental Toxicology” in (sixth edition, 2015).

OSHA: “.”

Teratology: “Developmental phase alters dosimetry-teratogenicity relationship for 2-methoxyethanol in CD-1 mice” (March 1994).

United States Census Bureau: “Maternity Leave and Employment Patterns of First-Time Mothers: 1961-2008” (, October 2011).