Dose-Response Relationships - Clinical Pharmacology - MSD Manual Professional Edition
Measurement of the relationship between the quantity of a substance or exposure to radiation (the dose) and its overall effect (the response) on an organism. Life-stage-dependent toxicity and dose-dependent toxicokinetics (TK) were Male and female rats were fed 2,4-D-fortified diets at doses to ppm Daily Ingested 2,4-D and Its Relationship With Levels in Dam Blood, Milk, dose and life stage can be used to define a scientifically sound and robust. In such cases, the standard notion of threshold, as defined by the NOAEL . From these 51 studies, dose-effect relationships were claimed by the .. Additional effects included a deficit in the sexual behavior of male rats.
This profile, also called inverted-U shape, is characterized by responses at intermediate dose s and a decreased response or no response observed at low- and high-exposure levels.
Also observed in the literature are U-shaped profiles with the highest responses at low- and high-exposure levels. In such cases, the standard notion of threshold, as defined by the NOAEL concept, is not inclusive of all potentially harmful effects. As clearly stated by Vandenberg et al. Thus, the standard approaches used for setting safe human and environmental exposure levels by extrapolation from high dose testing might not be applicable in case of NMDR profiles.
There is a class of toxicants i. The EDCs act through several modes of action to cause effects on sensitive tissues.
dose response relationship
As a result, EDCs can commonly act on many physiological systems in addition to endocrine tissues. Effects observed in sensitive target tissues can also be caused by exposure-related changes in mechanisms governing normal negative feedback regulation of endocrine tissues and hormone secretion; such effects may also influence the dose-response relationship depending on exposure duration.
With increasing awareness, more studies are being specifically designed to address whether the dose-response relationships for EDCs and other chemicals are described with an NMDR curve. As a result, NMDR relationships are being reported with an increasing frequency, which may have consequences for risk assessment.
As reported by Vandenberg et al. The work described in this manuscript aimed to 1 perform a focused literature review, 2 extract a representative set of observed NMDR relationships for some EDCs and 3 use that information to develop a methodology to assess whether such a reported dose-response relationship is sufficiently reliable in order to be used in risk assessments.
The screening analysis method evaluating the likelihood and the plausibility of the biological mechanisms involved was applied for each identified NMDR.
Our Stolen Future: Non-monotonic dose response curves
Then, a stepwise decision tree was developed as a tool to standardize analysis for data reliability of observed in vivo NMDR relationships for risk assessment. Many keywords related to EDCs i. All published articles outlining an NMDR relationship with a tested compound were selected. To determine whether the existence of an NMDR relationship was supported by the available data, a qualitative methodology was applied by considering the statistical strength and the biological plausibility of each reported NMDR profile.
To assess the statistical strength of NMDR profile, an appropriate statistical analysis based on individual results demonstrating the non-monotonic nature of each dose-response relationship is essential. There were cases in which a proper statistical analysis was not performed by the authors and individual data were poorly reported. Therefore, in these cases, it was difficult to confirm a posteriori that the observed relationships were statistically significant for a non-monotonic behavior.
For those cases, specific scoring criteria were applied to assess the strength of the NMDR relationships. This scoring criteria was derived from the identification criteria proposed by Calabrese and Baldwin [ 12 ] for hormesis a specific type of NMDR profile. Assessment of 2,4-D TK during the perinatal period is particularly important and informative in that expression of OAT1 does not reach full maturity in rats until approximately postnatal day PND 30 Buist et al.
Understanding systemic dosimetry during this critical period of development has improved both the design and interpretation of the extended 1-generation reproductive toxicity study Marty et al.What is Codependency, Really?
Finally, this TK data set provides useful insights not only for informing past and future toxicity test design and interpretation considerations for 2,4-D but also more broadly informs risk assessment implications for a spectrum of other low-molecular-weight environmental contaminants similarly subject to nonlinear TK behaviors.
Control diets were prepared using a similar procedure without 2,4-D.
The stability of 2,4-D in rodent chow was confirmed to be at least 27 days at the concentrations used in this study data not shown ; test diets were prepared and used within this stability period. Animals and animal husbandry. A total of 96 male and female Crl: Following health examinations and weighing, 9- to week-old rats were randomly assigned by body weight to treatment groups.
Adult parental, P1 animals were individually housed in wire-mesh cages suspended above catch pans. Pregnant and lactating females were kept in plastic litter boxes with ground corncob bedding from gestation day GD 19 until weaning of their litters on lactation day LD A pressure-activated lixit-valve watering system allowed ad libitum access to municipal water.
The institutional animal care and use committee of The Dow Chemical Company approved the experimental protocols, and the study followed good laboratory practice guidelines. Groups of 10 male and 10 female rats were initially fed diets supplying 0,, or ppm of 2,4-D. Due to excessive toxicity marked decreases in body weight and feed consumptionthe ppm dose was reduced to ppm on test day TD To optimize dose spacing, the ppm dose was simultaneously lowered to ppm. Throughout this study, the lower adjusted dietary concentrations are used to identify these dose groups.