Correlation of chemical structure with reproductive and developmental toxicity as it relates to the use of the threshold of toxicological concern

Laufersweiler, Michael C.; Gadagbui, Bernard; Abraham, Irene; Maier, Andrew; Willis, Alison; Scialli, Anthony R.; Carr, Gregory J.; Felter, Susan P.; Blackburn, Karen; Daston, George P.

doi:10.1016/j.yrtph.2011.09.004

Cited by 1,394 publications

(32 citation statements)

References 137 publications

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“…Each time, the contents of the ascending colon were collected from three gilts from each experimental group. In all experimental groups, the mycotoxins were administered at NOAEL (no observable adverse effect level) doses (Schlatter 2004;Boermans and Leung 2007;Laufersweiler et al 2012). The experiment was conducted over 42 days.…”

Section: Methodsmentioning

confidence: 99%

The genotoxicity of caecal water from gilts following experimentally induced Fusarium mycotoxicosis

et al. 2015

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ABSTRACT:The examination of caecal contents allows one to investigate the exposure of colon mucosa to dietary toxins and the chemical contaminants present in animal feed. The objective of the present study was to examine the influence of Fusarium mycotoxins (zearalenone, ZEN, and deoxynivalenol, DON), administered separately and as a mixture, on the genotoxicity of caecal water (CW) from gilts fed these mycotoxins. CW genotoxicity was evaluated with the comet assay using the LLC-PK1 porcine epithelial kidney cell line. It was shown that after the first week of the experiment, the presence of DON in animal feed led to increased CW genotoxicity in the proximal colon, while the presence of DON and ZEN + DON had a similar effect in the distal colon (ANOVA, P < 0.05). After the third week of experiment, elevated genotoxicity in the distal colon was observed for all experimental groups of gilts, and it was 62%, 52.4%, and 52.8% higher for ZEN-, DON-, and ZEN + DON-fed animals, respectively, than for control group animals. However, no effect on CW genotoxicity in the proximal colon was seen. After six weeks, the presence of ZEN in the proximal colon increased CW genotoxicity by 103% in comparison with the control group. In the distal colon, after the sixth week, CW genotoxicity in all groups of animals fed with mycotoxin was significantly (by 80% to 116%) higher than in the control group. ZEN and DON administered as a mixture did not lead to an increased genotoxicity compared to either agent administered separately. Generally, the mycotoxins clearly started to increase the genotoxicity of CW from the third week of administration.

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Section: Methodsmentioning

confidence: 99%

The genotoxicity of caecal water from gilts following experimentally induced Fusarium mycotoxicosis

et al. 2015

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“…(2011) 480 μg/day (0.008 mg/kg) Developmental toxicity Chemicals (UF: x500) Laufersweiler et al . (2012) 1122 μg/day (0.0187 mg/kg) Reproductive toxicity Chemicals (Class II) (UF: x100) Laufersweiler et al . (2012) 7860 μg/day (0.131 mg/kg) Reproductive toxicity Chemicals (Class I) (UF: x100) This table was derived from the reference by Stanard et al .…”

Section: Resultsmentioning

confidence: 99%

“…This approach is based on the threshold of below which "there would be no appreciable risk to human health" (Kroes et al, 2004). Several reports regarding TTC have been issued for DART (Bernauer et al, 2008;Laufersweiler et al, 2012;Stanard et al, 2015;Van Ravenzwaay et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Risk assessment of reproductive and developmental toxicity in eye-drop drugs: a consideration based on threshold of toxicological concern

Kurata

Kito

Sadamoto

et al. 2018

Fundam. Toxicol. Sci.

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-The systemic dose levels of eye-drop drugs are relatively low in comparison with that of systemic routes such as oral administration. We undertook overall risk assessment of eye-drop drugs for developmental and reproductive toxicity (DART) by comparing the estimated systemic dose level of eyedrop drugs with the known threshold of toxicological concern (TTC) for DART. The systemic dose level of eye-drop drugs in human were estimated to be 0.0005 to 0.05 mg/kg/day on the assumption of 0.01% to 1% of eye drop formulation, 0.04 mL/eye/time of instillation volume, and 60 kg body weight. The TTCs for DART ranged from 0.003 mg/day (0.00005 mg/kg/day; for anticacer drugs) to 7.860 mg/day (0.131 mg/kg/day). Therefore, the range of estimated systemic dose level of eye-drop drugs was almost overlapped with known TTC values for DART, excepting for that applied to the anticacer drugs. These knowledge simply indicates the safety of eye-drop drugs for DART from a view pont of absolute dosage levels, implying allowance of case by case basis planning non-clinical DART study.

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“…Moving away from the cancer bioassays, analyzing a reference database of more than 600 substances tested in more than 2,900 sub-chronic and chronic toxicity studies, Munro et al (1990Munro et al ( , 1996Munro et al ( , 1999 Cheeseman et al, 1999;Felter et al, 2009;Müller et al, 2006 General toxicity 0.025 -1 (depending on Cramer classes) Munro et al, 1996Munro et al, , 1999 Munro et al, 1996Munro et al, , 1999Escher et al, 2010;Bernauer et al, 2008Genotoxicity 0.025 -2 Rulis 1986, 1989Kroes et al, 2005;Müller et al, 2006 Carcinogenicity (genotoxic) 0.0025 Kroes et al, 2005;Cheeseman et al, 1999 Carcinogenicity (non-genotoxic) 0.025 -0.75 Kroes et al, 2005; (depending on Ames test and acute toxicity) Cheeseman et al, 1999 Acute toxicity (inhalation) 4 -1,000 μg/m 3 Grant et al, 2007;Escher et al, 2010 Neurotoxicity 0.3 Munro andKroes, 1998;Kroes et al, 2000 Developmental toxicity 1 a -8 -131 Munro and Kroes, 1998; (depending on Cramer class) Bernauer et al, 2008;0.5 -1 μg/m 3 (inhalation) van Ravenzwaay et al, 2011;Laufersweiler et al 2012 Reproductive toxicity 1 -100 Bernauer et al, 2008;van Ravenzwaay et al, 2011van Ravenzwaay et al, , 2012van Ravenzwaay et al, , 2017 Estrogenic endocrine disruption 0.025 Kroes et al, 2000 Immunotoxicity 0.15 -1,000 Kroes et al, 2000;Hartung and Corsini, 2013 Skin sensitization (dermal) 0.91 -900 μg/cm 2 Sa...…”

Section: IImentioning

confidence: 99%

“…The same group (van Ravenzwaay et al, 2012) identified 104 rabbit studies with values for maternal and developmental toxicity (48 from BASF, 56 from literature) using the 5 th percentile for developmental toxicity of these mostly active ingredients, a TTC value of 4 μg/ kg bw/d was calculated using a safety factor of 500 to account for the relatively small database. Laufersweiler et al (2012) expanded this approach to 300 chemicals with reproductive and developmental data, deducing a TTC of 6 μg/kg bw/day. These reports already showed very consistent TTC for reproductive and developmental toxicity.…”

Section: Threshold Setting In Toxicologymentioning

confidence: 99%

Thresholds of Toxicological Concern – Setting a threshold for testing below which there is little concern

Hartung

2017

ALTEX

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Correlation of chemical structure with reproductive and developmental toxicity as it relates to the use of the threshold of toxicological concern

Cited by 1,394 publications

References 137 publications

The genotoxicity of caecal water from gilts following experimentally induced Fusarium mycotoxicosis

The genotoxicity of caecal water from gilts following experimentally induced Fusarium mycotoxicosis

Risk assessment of reproductive and developmental toxicity in eye-drop drugs: a consideration based on threshold of toxicological concern

Thresholds of Toxicological Concern – Setting a threshold for testing below which there is little concern

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