A characterization of dose–response relationships for developmental effects of bisphenol A (BPA) in the low dose range

2015 ◽  
Vol 238 (2) ◽  
pp. S128
Author(s):  
L. Molander ◽  
A. Beronius ◽  
A. Hanberg ◽  
M. Ågerstrand ◽  
C. Rudén
Keyword(s):  
Bisphenol A ◽  
Dose Response ◽  
Low Dose ◽  
Dose Range ◽  
Developmental Effects

Evidence for dose and dose rate effects in human and animal radiation studies

2018 ◽  
Vol 47 (3-4) ◽  
pp. 97-112 ◽  
Author(s):  
M.P. Little
Keyword(s):  
Dose Rate ◽  
Dose Response ◽  
Low Dose ◽  
Atomic Bomb ◽  
Dose Range ◽  
Quadratic Model ◽  
Linear Quadratic ◽  
Dose Rates ◽  
Atomic Bomb Survivors ◽  
Linear Quadratic Model

For stochastic effects such as cancer, linear-quadratic models of dose are often used to extrapolate from the experience of the Japanese atomic bomb survivors to estimate risks from low doses and low dose rates. The low dose extrapolation factor (LDEF), which consists of the ratio of the low dose slope (as derived via fitting a linear-quadratic model) to the slope of the straight line fitted to a specific dose range, is used to derive the degree of overestimation (if LDEF > 1) or underestimation (if LDEF < 1) of low dose risk by linear extrapolation from effects at higher doses. Likewise, a dose rate extrapolation factor (DREF) can be defined, consisting of the ratio of the low dose slopes at high and low dose rates. This paper reviews a variety of human and animal data for cancer and non-cancer endpoints to assess evidence for curvature in the dose response (i.e. LDEF) and modifications of the dose response by dose rate (i.e. DREF). The JANUS mouse data imply that LDEF is approximately 0.2–0.8 and DREF is approximately 1.2–2.3 for many tumours following gamma exposure, with corresponding figures of approximately 0.1–0.9 and 0.0–0.2 following neutron exposure. This paper also cursorily reviews human data which allow direct estimates of low dose and low dose rate risk.

Weight of the Evidence Evaluation of Low-Dose Reproductive and Developmental Effects of Bisphenol A

2004 ◽  
Vol 10 (5) ◽  
pp. 875-921 ◽  
Author(s):  
George M. Gray ◽  
Joshua T. Cohen ◽  
Gerald Cunha ◽  
Claude Hughes ◽  
Ernest E. McConnell ◽  
...  
Keyword(s):  
Bisphenol A ◽  
Low Dose ◽  
Developmental Effects ◽  
Evidence Evaluation

scholarly journals Low-dose effects of bisphenol A on early sexual development in male and female rats

Reproduction ◽  
2014 ◽  
Vol 147 (4) ◽  
pp. 477-487 ◽  
Author(s):  
Sofie Christiansen ◽  
Marta Axelstad ◽  
Julie Boberg ◽  
Anne Marie Vinggaard ◽  
Gitte Alsing Pedersen ◽  
...  
Keyword(s):  
Bisphenol A ◽  
Sexual Development ◽  
Low Dose ◽  
Dose Range ◽  
Daily Intake ◽  
Reproductive Organ ◽  
Female Rats ◽  
Male And Female ◽  
Male And Female Rats ◽  
Pregnancy And Lactation

Bisphenol A (BPA) is widely detected in human urine and blood. BPA has been reported to impair many endpoints for reproductive and neurological development; however, it is controversial whether BPA has effects in the microgram per kilogram dose range. The aim of the current study was to examine the influence of BPA on early sexual development in male and female rats at dose levels covering both regulatory no observed adverse effect levels (NOAELs) (5 and 50 mg/kg bw per day) as well as doses in the microgram per kilogram dose range (0.025 and 0.25 mg/kg bw per day). Time-mated Wistar rats (n=22) were gavaged during pregnancy and lactation from gestation day 7 to pup day 22 with 0, 0.025, 0.25, 5 or 50 mg/kg bw per day BPA. From 0.250 mg/kg and above, male anogenital distance (AGD) was significantly decreased, whereas decreased female AGD was seen from 0.025 mg/kg bw per day and above. Moreover, the incidence of nipple retention in males appeared to increase dose relatedly and the increase was statistically significant at 50 mg/kg per day. No significant changes in reproductive organ weights in the 16-day-old males and females and no signs of maternal toxicity were seen. The decreased AGD at birth in both sexes indicates effects on prenatal sexual development and provides new evidence of low-dose adverse effects of BPA in rats in the microgram per kilogram dose range. The NOAEL in this study is clearly below 5 mg/kg for BPA, which is used as the basis for establishment of the current tolerable daily intake (TDI) by EFSA; thus a reconsideration of the current TDI of BPA appears warranted.

scholarly journals Toxic Responses Induced at High Doses May Affect Benchmark Doses

Dose-Response ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 155932582091960 ◽  
Author(s):  
Jürg A. Zarn ◽  
Ursina A. Zürcher ◽  
H. Christoph Geiser
Keyword(s):  
Dose Response ◽  
Low Dose ◽  
Dose Range ◽  
Reference Points ◽  
Benchmark Dose ◽  
High Dose ◽  
Low Doses ◽  
Confidence Bounds ◽  
Lower Confidence Bounds ◽  
Dose Responses

To derive reference points (RPs) for health-based guidance values, the benchmark dose (BMD) approach increasingly replaces the no-observed-adverse-effect level approach. In the BMD approach, the RP corresponds to the benchmark dose lower confidence bounds (BMDLs) of a mathematical dose–response model derived from responses of animals over the entire dose range applied. The use of the entire dose range is seen as an important advantage of the BMD approach. This assumes that responses over the entire dose range are relevant for modeling low-dose responses, the basis for the RP. However, if part of the high-dose response was unnoticed triggered by a mechanism of action (MOA) that does not work at low doses, the high-dose response distorts the modeling of low-dose responses. Hence, we investigated the effect of high-dose specific responses on BMDLs by assuming a low- and a high-dose MOA. The BMDLs resulting from modeling fictitious quantal data were scattered over a broad dose range overlapping with the toxic range. Hence, BMDLs are sensitive to high-dose responses even though they might be irrelevant to low-dose response modeling. When applying the BMD approach, care should be taken that high-dose specific responses do not unduly affect the BMDL that derives from low doses.

Dose-response relationships in phase I trials: Are patients treated at lower doses at a disadvantage?

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2519-2519
Author(s):  
R. Jain ◽  
D. Hong ◽  
A. Naing ◽  
J. Wheler ◽  
J. J. Lee ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Response ◽  
Dose Group ◽  
Low Dose ◽  
Dose Range ◽  
Cancer Therapeutics ◽  
Biologic Agent ◽  
High Dose ◽  
Phase I Trials ◽  
Dose Patient

2519 Background: A major goal of phase I trials is to determine a drug's maximally tolerated dose (MTD). However, it has been argued that low-dose patient cohorts are at a disadvantage given the clear dose/response relationships seen with cytotoxics. Since an increasing number of targeted/biologic agents are entering the clinic, and the dose/response relationship of these drugs is less clear, we analyzed response versus benefit for patients on phase I trials. Methods: We evaluated 71 consecutive trials treating 1,420 patients with solid tumors or lymphoma from August 2004 to August 2008 in the Department of Investigational Cancer Therapeutics at M.D. Anderson for inclusion in our analysis. Twenty-four trials treating 687 patients met criteria (systemic therapy that has reached an MTD or a maximum test dose). 97.7% of these patients received a targeted/biologic drug. Patients were assigned to low (≤25%), medium (25–75%), or high dose (≥75%), where dose range = maxium - minimum dose for each study (for ≤ MTD analysis, max dose = MTD if it was achieved). Time on treatment (TOT), progression free survival (PFS), overall survival (OS), and response (complete response = CR, partial response = PR, stable disease = SD, progressive disease = PD) were assessed. Results: Of all comers (n = 683), the low-dose group stayed on treatment significantly longer than the high-dose group, primarily due to increased toxicity at higher doses. In ≤ MTD subgroup analysis (n = 588), there was also a trend for the low-dose group to stay on treatment longer (p = 0.06). PFS and OS were similar among groups. Favorable responses (CR/PR/SD) were as common for low dose as other dose groups. Conclusions: In a large cohort of pts treated on phase I studies that predominantly included one or more targeted/biologic agent, there was no downside to being on low versus medium or high doses. These data should alleviate concerns about relative lack of benefit for low-dose patient cohorts on phase I trials, and support the notion that dose/response relationships for targeted agents may be less clear than for cytotoxics. [Table: see text] No significant financial relationships to disclose.

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