This presentation is based on Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for Industry. (2015, September). Retrieved April 27, 2018, from US Food and Drug Administration. 

1. Nonclinical Evaluation: Endocrine
Related Drug Toxicity
- Alex Thomas
May 04, 2018

2. 2
Claude Bernard
(12 July 1813- 10 February 1878)
Friedrich Gustav Jakob Henle
(9 July 1809 - 13 May 1885)
Gustave-Édouard Laguesse
(23 April 1861 – 6 November 1927)
 “Affecting within” or “Internal Secretion”
 Chemical messenger system
Introduction:
Ref: Bioetymology, 2018; Anatomy Words, 2018

3. Introduction (Contd.)
Endocrine Signaling:
 Central nervous system via the hypothalamus
 Hormones produced by the hypothalamus act on:
– gonads to produce androgens or estrogens
– thyroid gland to produce thyroid hormones
– adrenal glands to produce corticosteroids
 Negative feedback mechanism
3
Ref: D.Wallace, 2012

4. Introduction (Contd.)
Hormonal Signaling:
 Hormone binding - nuclear receptor transcription factors
(androgen receptor, estrogen receptor, thyroid receptor (TR),
or glucocorticoid receptor)
 Receptor activation - alters - expression of specific genes-
altered protein levels - cellular function
 Forty-eight receptors identified (humans)
4
Ref: D.Wallace, 2012

5.  Mimicking or enhancing
 Blocking a hormone receptor
 Affecting the synthesis, transport, metabolism, binding
action or excretion
Loss of normal tissue function, development, growth, or
reproduction
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Ref: Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for Industry, 2015.
Endocrine Toxicity:

6. Repeat-Dose Toxicity Studies:
 In two species (rodent and non rodent)
 For drugs intended for chronic usage - up to 6 (rodent) or 9
(non rodent) months
 Endpoints include - changes in organ weight, gross organ
pathology, clinical chemistry, and histopathology
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Ref: Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for Industry, 2015.

7. Sensitive Organs:
 Thyroid gland
 Adrenal glands
 Reproductive organs
 Pituitary gland
7
Ref: Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for Industry, 2015.

8. Example: Estrogenic Drugs
 Increased ovarian and uterine weight
 Endometrial stimulation
 Mammary gland stimulation
 Decreased thymus weight and involution
 Increased bone mineral density
8
Ref: Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for Industry, 2015.

9. DART Studies :
Developmental stages (e.g., gestational, neonatal, peripubertal)
are particularly sensitive to endocrine effects, endpoints include:
 Vaginal patency
 Preputial separation
 Anogenital distance (for male offspring)
 Nipple retention
 The reproductive performance of offspring -neuroendocrine
effects
9
Ref: Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for Industry, 2015.

10. Carcinogenicity Studies:
 Persistent disruption of Hypothalamic-pituitary adrenal
/gonadal /thyroidal axis(es) and neoplasms
10
Ref: Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for Industry, 2015.

11. Test Articles:
 Alteration of :
– Sex hormones
– Hypothalamic-pituitary-adrenal hormones
– Thyroid hormones
– Hormones involved in feedback regulation of endocrine
systems
11
Ref: Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for Industry, 2015.

12. Nonclinical Assessments:
 Receptor-Binding Assays
 Pharmacology Studies
 Repeat-Dose Toxicity Studies
 Developmental and Reproductive Toxicity
 Carcinogenicity Studies
12
Ref: Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for Industry, 2015.

13. Additional Studies ?
 Data on adverse endocrine-related effects?
 Is the drug proposed for use in a population not studied in
standard toxicity studies ?
 Clinical systemic exposure - near or above NOAEL for
endocrine effects in animals ?
13
Ref: Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for Industry, 2015.

14. Additional Assessments:
 Mechanistic Studies
 Nonclinical Juvenile Studies
 Clinical Studies
14
Ref: Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for Industry, 2015.

15. Summary :
The standard comprehensive test battery is sufficient to
identify endocrine related toxicity, depending on the
outcome, additional nonclinical studies may be warranted.
15

16. Bibliography:
 Anonymous. (2018). Anatomy Words. Retrieved May 03, 2018, from
Endocrine: http://anatomyalmanac.blogspot.in/2007/10/endocrine-
from-greek-endon-within-and.html
 Anonymous. (2018). endocrine. Retrieved May 03, 2018, from
bioetymology:
http://bioetymology.blogspot.in/2011/10/endocrine.html
 D.Wallace, A. (2012). Chapter Four:Toxic Endpoints in the Study of
Human Exposure to Environmental Chemicals. In E. Hodgson, Progress
in Molecular Biology and Translational Science (pp. 89-115). Elsevier.
 Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for
Industry. (2015, September). Retrieved April 27, 2018, from US Food
and Drug Administration.
16

17. Thank You