Critique of dose response in carcinogenesis

A few landmarks in the development of dose response in toxicology are presented, with an explanation of why dose should only be considered on a logarithmic scale. Examples are shown, illustrating that the current practice of labeling dose-response curves for carcinogenesis as supralinear, linear or sublinear, is meaningless unless the dose-response scales are defined. Since many reports labeling such curves as supralinear, linear, or sublinear are carried out with dose on a linear scale, the scientific significance of the shape of the curve is obscured. Examples of dose-response curves for carcinogenesis from 2-acetylaminofluorene, N-nitrosodiethylamine, aflatoxins, and radium are shown. In addition, more than 500 National Toxicology Program Technical Reports (NTP-TR) on carcinogenicity were examined; from this database, three groups of studies were selected. The first group consisted of those studies in which the lowest dose produced no tumors and the study had a positive dose response. The second group consisted of those studies with three or more doses, with a positive dose response producing tumors, but in which there were no tumors in the control group. The third group of more than 50 studies was from NTP-TR-00 to NTP-TR-52 that had only two data points with a positive dose response. These studies were all evaluated on the Rozman et al. scale, since it conforms to the laws of nature and allows evaluation of all doses. It was observed that virtually all of these NTP-TR carcinogenicity studies show a linear response when dose is on this logarithmic scale; a clear threshold for carcinogenicity is typical for nearly all of these chemicals. An exponential dose-response curve was a better fit for a few, but experimental error could account for this deviation from linearity. It is pointed out that there is strong experimental evidence that the mere presence of DNA adducts does not necessarily lead to tumor production. Hormesis probably applies to carcino-genesis and proof of this will require abandoning the no threshold concept. Experiments showing that cumulative dose is a better metric than daily dose may require reevaluating almost all carcinogenicity studies.

Download Full-text

Influence of decompression sickness on vasocontraction of isolated rat vessels

Journal of Applied Physiology ◽

10.1152/japplphysiol.00139.2015 ◽

2016 ◽

Vol 120 (7) ◽

pp. 784-791 ◽

Cited By ~ 10

Author(s):

Aleksandra Mazur ◽

Kate Lambrechts ◽

Qiong Wang ◽

Marc Belhomme ◽

Michael Theron ◽

...

Keyword(s):

Dose Response ◽

Clinical Symptoms ◽

Decompression Sickness ◽

Vascular Dysfunction ◽

Plasma Concentrations ◽

Mesenteric Arteries ◽

Control Group ◽

Response Curves ◽

Endothelin 1 ◽

Dose Response Curves

Studies conducted in divers indicate that endothelium function is impaired following a dive even without decompression sickness (DCS). Our previous experiment conducted on rat isolated vessels showed no differences in endothelium-dependent vasodilation after a simulated dive even in the presence of DCS, while contractile response to phenylephrine was progressively impaired with increased decompression stress. This study aimed to further investigate the effect of DCS on vascular smooth muscle. Thirty-two male Sprague-Dawley rats were submitted to the same hyperbaric protocol and classified according to the severity of DCS: no-DCS (without clinical symptoms), mild-DCS, or severe-DCS (dead within 1 h). A control group remained at atmospheric pressure. Isometric tension was measured in rings of abdominal aorta and mesenteric arteries. Single dose contraction was assessed with KCl solution. Dose-response curves were obtained with phenylephrine and endothelin-1. Phenylephrine-induced contraction was observed in the presence of antioxidant tempol. Additionally, plasma concentrations of angiotensin II, angiotensin-converting enzyme, and thiobarbituric acid reactive substances (TBARS) were assessed. Response to phenylephrine was impaired only among mild-DCS in both vessels. Dose-response curves to endothelin-1 were impaired after mild-DCS in mesenteric and severe-DCS in aorta. KCl-induced contraction was affected after hyperbaric exposure regardless of DCS status in aorta only. These results confirm postdive vascular dysfunction is dependent on the type of vessel. It further evidenced that vascular dysfunction is triggered by DCS rather than by diving itself and suggest the influence of circulating factor/s. Diving-induced impairment of the L-type voltage-dependent Ca2+ channels and/or influence of renin-angiotensin system is proposed.

Download Full-text

Biphasic modulation of pituitary sensitivity to GnRH by oestrogens: the effects of A- and D-ring substitution on LH release in cultured pituitary cells

Acta Endocrinologica ◽

10.1530/acta.0.1070317 ◽

1984 ◽

Vol 107 (3) ◽

pp. 317-327 ◽

Cited By ~ 7

Author(s):

G. Emons ◽

R. Knuppen ◽

P. Ball ◽

K.J. Catt

Keyword(s):

Dose Response ◽

High Sensitivity ◽

Female Rats ◽

Pituitary Cells ◽

Response Curves ◽

Methyl Group ◽

Lh Release ◽

Dose Response Curves ◽

Sensitizing Effect ◽

Almost All

Abstract. The sensitizing effect of oestrogens on GnRH-stimulated LH release was evaluated in pituitary cells from adult female rats, cultured for 2 days in the presence of 10−13 to 10−6 m concentrations of oestradiol and selected A- and D-ring modified oestrogens. With almost all steroids tested, bell-shaped dose-response curves with comparable LH-maxima but different EDmax values were obtained for the LH response to a submaximal GnRH stimulus (5 × 10−10 m). Maximal LH response to 5 × 10−10 m GnRH were found at the following oestrogen concentrations: oestradiol and 4-hydroxyoestradiol = 10−11 m; 2-methyloestradiol = 10−9 m; 2-hydroxyoestradiol = 10−8 m; with 4-methyloestradiol no significant maximum was observed. When cells were pretreated with 10−13, 10−11 and 10−9 m oestradiol, or 4-hydroxyoestradiol, or 2-hydroxyoestradiol, and exposed to increasing concentrations of GnRH (10−11 to 10−7 m), an almost 10-fold decrease in the ED50 for GnRH was observed after pretreatment with 10−11 m oestradiol and 4-hydroxyoestradiol. With 2-hydroxyoestradiol at this concentration, the sensitizing effect was much less pronounced. Increasing the steroid concentration to 10−9 m slightly decreased the effect of oestradiol and 4-hydroxyoestradiol, whereas it increased the effect of 2-hydroxyoestradiol. Thus, at the target cell 4-hydroxyoestradiol has the same potency as oestradiol, while 2-hydroxyoestradiol is significantly less active. The sensitizing effect of oestradiol is only slightly decreased by the presence of a methyl group in position 2, but is markedly reduced by a methyl group in position 4. Our results also demonstrate the high sensitivity of the pituitary to oestrogen-induced enhancement of GnRH-stimulated gonadotrophin release, as well as the decrease of the positive effect at high oestrogen concentrations. The bell-shaped dose-response curves for oestrogen action should be taken into account when evaluating the effects of oestrogens and their derivatives upon gonadotrophin release from the pituitary gland.

Download Full-text

Dose-response Curves in the Fibrin Plate Assay Fibrinolytic Activity of Proteases

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647705 ◽

1974 ◽

Vol 32 (02/03) ◽

pp. 356-365 ◽

Cited By ~ 12

Author(s):

F Haverkate ◽

D. W Traas

Keyword(s):

Dose Response ◽

Fibrinolytic Activity ◽

Enzyme Concentration ◽

Response Curves ◽

Agar Gel ◽

Porcine Tissue ◽

Plate Assay ◽

Fibrin Plate ◽

Different Types ◽

Dose Response Curves

SummaryIn the fibrin plate assay different types of relationships between the dose of applied proteolytic enzyme and the response have been previously reported. This study was undertaken to determine whether a generally valid relationship might exist.Trypsin, chymotrypsin, papain, the plasminogen activator urokinase and all of the microbial proteases investigated, including brinase gave a linear relationship between the logarithm of the enzyme concentration and the diameter of the circular lysed zone. A similar linearity of dose-response curves has frequently been found by investigators who used enzyme plate assays with substrates different from fibrin incorporated in an agar gel. Consequently, it seems that this linearity of dose-response curves is generally valid for the fibrin plate assay as well as for other enzyme plate bioassays.Both human plasmin and porcine tissue activator of plasminogen showed deviations from linearity of semi-logarithmic dose-response curves in the fibrin plate assay.

Download Full-text

BIOASSAY OF THYROID HORMONE USING HYPOTHYROID TADPOLES

Acta Endocrinologica ◽

10.1530/acta.0.0410143 ◽

1962 ◽

Vol 41 (1) ◽

pp. 143-153 ◽

Cited By ~ 2

Author(s):

U. Henriques

Keyword(s):

Thyroid Hormone ◽

Dose Response ◽

Developmental Rate ◽

Response Curves ◽

Sodium Salts ◽

Dose Response Curves

ABSTRACT A bioassay of thyroid hormone has been developed using Xenopus larvae made hypothyroid by the administration of thiourea. Only tadpoles of uniform developmental rate were used. Thiourea was given just before the metamorphotic climax in concentrations that produced neoteni in an early metamorphotic stage. During maintained thiourea neotoni, 1-thyroxine and 1-triiodothyronine were added as sodium salts to the water for three days and at the end of one week the stage of metamorphosis produced was determined. In this way identical dose-response curves were obtained for the two compounds. No qualitative differences between their effects were noted except that triiodothyronine seemed more toxic than thyroxine in equivalent doses. Triiodothyronine was found to be 7–12 times as active as thyroxine.

Download Full-text

Dose Response Curves for Microwave Ablation in the Cardioplegia-Arrested Porcine Heart

The Heart Surgery Forum ◽

10.1532/hsf98.20051011 ◽

2005 ◽

Vol 8 (4) ◽

pp. E269-E274 ◽

Cited By ~ 1

Author(s):

Sydney L. Gaynor ◽

Gregory D. Byrd ◽

Michael D. Diodato ◽

Yosuke Ishii ◽

Anson M. Lee ◽

...

Keyword(s):

Dose Response ◽

Microwave Ablation ◽

Response Curves ◽

Porcine Heart ◽

Dose Response Curves

Download Full-text

Modeling Nonmonotonic Dose-Response Curves

10.21236/ada391664 ◽

2001 ◽

Author(s):

Quinton J. Nottingham ◽

Jeffrey B. Birch ◽

Barry A. Bodt

Keyword(s):

Dose Response ◽

Response Curves ◽

Dose Response Curves

Download Full-text

Comment Concerning the Effects of Light Intensity on Melatonin Suppression in the Review “Light Modulation of Human Clocks, Wake, and Sleep” by A. Prayag et al.

Clocks & Sleep ◽

10.3390/clockssleep3010011 ◽

2021 ◽

Vol 3 (1) ◽

pp. 181-188

Author(s):

Peter Bracke ◽

Eowyn Van de Putte ◽

Wouter R. Ryckaert

Keyword(s):

Phase Shift ◽

Light Intensity ◽

Dose Response ◽

Light Modulation ◽

Response Curves ◽

Practical Applications ◽

Circadian Phase ◽

Melatonin Suppression ◽

Dose Response Curves ◽

Circadian Phase Shift

Dose-response curves for circadian phase shift and melatonin suppression in relation to white or monochromatic nighttime illumination can be scaled to melanopic weighed illumination for normally constricted pupils, which makes them easier to interpret and compare. This is helpful for a practical applications.

Download Full-text