This paper is an addendum to a 2016 paper outlining pitfalls and parameters to consider in the co... more This paper is an addendum to a 2016 paper outlining pitfalls and parameters to consider in the conduct of food additive research with carrageenan (Fd. Chem. Tox. 87, 31-44 (2016)). The literature on the food additive, "carrageenan," contains many publications which either erroneously misuse the name, carrageenan, for a sample which is not carrageenan, but "degraded carrageenan" or "poligeenan" and also conduct studies without understanding the physical/chemical properties of carrageenan. Degraded carrageenan and poligeenan are not food additives and have a completely different physical/chemical and toxicological properties from carrageenan. Two recent publication examples, one in vivo and one in vitro, demonstrate the serious misunderstanding promulgated by incorrect sample identity/purity and poor study conduct. These new publication examples reiterate the problems in the literature summarized by the Weiner (2016). It is important to have thorough, rigorous peer review of all studies using carrageenan in vivo or in vitro.
Amid growing efforts to advance the replacement, reduction, and refinement of the use of animals ... more Amid growing efforts to advance the replacement, reduction, and refinement of the use of animals in research, there is a growing recognition that in vitro testing of medical devices can be more effective, both in terms of cost and time, and also more reliable than in vivo testing. Although the technological landscape has evolved rapidly in support of these concepts, regulatory acceptance of alternative testing methods has not kept pace. Despite the acceptance by regulators of some in vitro tests (cytotoxicity, gene toxicity, and some hemocompatibility assays), many toxicity tests still rely on animals (irritation, sensitization, acute toxicity, reproductive/developmental toxicity), even where other industrial sectors have already abandoned them. Bringing about change will require a paradigm shift in current approaches to testing - and a concerted effort to generate better data on risks to human health from exposure to leachable chemicals from medical devices, and to boost confidence...
In Vitro Cellular Developmental Biology Journal of the Tissue Culture Association, May 1, 1992
Sodium butyrate (NaB), a 4-carbon fatty acid, has been reported to activate the metallothionein (... more Sodium butyrate (NaB), a 4-carbon fatty acid, has been reported to activate the metallothionein (MT) gene in certain carcinoma cell lines. Because the effects of NaB are dependent on the cell type investigated, this study was conducted to determine if NaB and its homologues induce MT in rat primary hepatocyte cultures. Hepatocytes were grown on monolayer for 12 h and subsequently treated with formate, acetate, propionate (NaP), NaB, and valeric acid for 10 to 58 h. To examine their interaction with known MT inducers, cadmium (Cd), zinc (Zn), or dexamethasone (Dex) were added to some cultures. MT protein in the cells was quantitated by the Cd-hemoglobin assay; MT-1 mRNA was analyzed by Northern blot hybridizations with oligonucleotide probes, and quantitated by slot-blot analysis. Among the 1 to 5 carbon carboxylic acids, only NaP (3 carbon) and NaB (4 carbon) induced MT. NaP and NaB alone produced a moderate increase in MT two- to fourfold over control), but when combined with Cd or Dex, an additive increase was observed. However, when combined with Zn, a synergistic increase was detected. NaB and Zn synergistically increased MT protein, but produced only an additive increase in MT mRNA, suggesting the involvement of some posttranscriptional event(s) in the NaB-Zn induction of MT. In conclusion, NaP and NaB induced MT in normal cultured rat hepatocytes, producing an additive increase in MT protein with Cd and Dex, and a synergistic increase in MT protein with Zn.
... of Phenolsulfonphthalein1 NASR H. ANAIZI2 and JULIUS J. COHEN Department of Physiology. ... 1... more ... of Phenolsulfonphthalein1 NASR H. ANAIZI2 and JULIUS J. COHEN Department of Physiology. ... 1978 ABSTRACT Anaizi, Nasr H. and Julius J. Cohen: The ef-fects of 2,3, 7,8-tetrach!orodibenzo-p-dioxin on the renal tubular secretion of phenolsulfon-phtha!ein. J. Pharmacol. ...
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2015
Carrageenan (CGN) is widely used in the food manufacturing industry as an additive that stabilize... more Carrageenan (CGN) is widely used in the food manufacturing industry as an additive that stabilizes and thickens food products. Standard animal safety studies in which CGN was administered in diet showed no adverse effects. However, several in vitro studies have reported that intestinal inflammation is caused by CGN and that this effect is mediated through Toll-Like-Receptor 4 (TLR4). The purpose of this study was to evaluate the ability of different types of CGN to bind and activate TLR4 signaling. To accomplish this a TLR4/MD-2/CD14/NFκB/SEAP reporter construct in a HEK293 cell line was used. The reporter molecule, secretable alkaline phosphatase (SEAP), was measured as an indicator of TLR4 activation. The test compounds were exposed to this system at concentrations of 0.1, 1, 10, 50, 100, 500, 1000, and 5000 ng/mL for 24 h. Cytotoxicity was evaluated following the 24 h exposure period by LDH leakage and ATP. CGN binding to serum proteins was characterized by Toluidine Blue. The re...
Toxicological sciences : an official journal of the Society of Toxicology, 2001
The cyclic siloxane octamethylcyclotetrasiloxane (D4) and the linear siloxane hexamethyldisiloxan... more The cyclic siloxane octamethylcyclotetrasiloxane (D4) and the linear siloxane hexamethyldisiloxane (HMDS) have numerous industrial and consumer applications and thus have the potential for human exposure. The present study was undertaken to examine potential estrogenic and antiestrogenic activities of D4 and HMDS. To address potential differences in sensitivity between rat strains the study used both Sprague-Dawley (SD) and Fischer 344 (F-344) rats. Estrogenicity of the test compounds was determined by measuring absolute and relative uterine weights in immature rats and by monitoring uterine epithelial cell height. In order to place the data obtained for D4 into perspective relative to strong and weak estrogenic compounds, the response produced by D4 at 0, 10, 50, 100, 250, 500, and 1000 mg/kg/day was compared to responses produced by ethinyl estradiol (EE) (1, 3, 10, or 30 microg/kg/day), diethylstilbestrol dipropionate (DES-DP) (0.5, 1.5, 5, 15 microg/kg/day), and coumestrol (CE) ...
Distribution of Cd to various organs following iv administration of CdCl2 (3.5 mg Cd/kg) resulted... more Distribution of Cd to various organs following iv administration of CdCl2 (3.5 mg Cd/kg) resulted in more than 43% of total tissue Cd accumulating in the liver. In contrast, after CdMT administration (0.5 mg Cd/kg), only 1% of the Cd was found in liver. Rats administered CdCl2 (1.0 mg Cd/kg) had hepatic MT values 30-fold greater than controls and a hepatic Cd concentration of 17 micrograms/g. In comparison, rats treated with CdMT (0.4 mg Cd/kg) had hepatic MT concentrations 7-fold greater than controls and a hepatic Cd concentration of 0.80 micrograms/g. However, when hepatic MT levels were normalized to tissue Cd concentrations, induction of MT by CdMT was 5-fold greater than by CdCl2. Northern and slot-blot analyses of mRNA showed that both CdCl2 and CdMT coordinately increased MT mRNA. These data suggest that both CdMT and CdCl2 increase hepatic MT by similar mechanisms. A dose-response increase in MT produced by CdCl2 indicated a biphasic response, with low doses producing relat...
Since March 2013, animal use for cosmetics testing for the European market has been banned. This ... more Since March 2013, animal use for cosmetics testing for the European market has been banned. This requires a renewed view on risk assessment in this field. However, in other fields as well, traditional animal experimentation does not always satisfy requirements in safety testing, as the need for human-relevant information is ever increasing. A general strategy for animal-free test approaches was outlined by the US National Research Council`s vision document for Toxicity Testing in the 21st Century in 2007. It is now possible to provide a more defined roadmap on how to implement this vision for the four principal areas of systemic toxicity evaluation: repeat dose organ toxicity, carcinogenicity, reproductive toxicity and allergy induction (skin sensitization), as well as for the evaluation of toxicant metabolism (toxicokinetics) (Fig. 1). CAAT-Europe assembled experts from Europe, America and Asia to design a scientific roadmap for future risk assessment approaches and the outcome was...
This paper is an addendum to a 2016 paper outlining pitfalls and parameters to consider in the co... more This paper is an addendum to a 2016 paper outlining pitfalls and parameters to consider in the conduct of food additive research with carrageenan (Fd. Chem. Tox. 87, 31-44 (2016)). The literature on the food additive, "carrageenan," contains many publications which either erroneously misuse the name, carrageenan, for a sample which is not carrageenan, but "degraded carrageenan" or "poligeenan" and also conduct studies without understanding the physical/chemical properties of carrageenan. Degraded carrageenan and poligeenan are not food additives and have a completely different physical/chemical and toxicological properties from carrageenan. Two recent publication examples, one in vivo and one in vitro, demonstrate the serious misunderstanding promulgated by incorrect sample identity/purity and poor study conduct. These new publication examples reiterate the problems in the literature summarized by the Weiner (2016). It is important to have thorough, rigorous peer review of all studies using carrageenan in vivo or in vitro.
Amid growing efforts to advance the replacement, reduction, and refinement of the use of animals ... more Amid growing efforts to advance the replacement, reduction, and refinement of the use of animals in research, there is a growing recognition that in vitro testing of medical devices can be more effective, both in terms of cost and time, and also more reliable than in vivo testing. Although the technological landscape has evolved rapidly in support of these concepts, regulatory acceptance of alternative testing methods has not kept pace. Despite the acceptance by regulators of some in vitro tests (cytotoxicity, gene toxicity, and some hemocompatibility assays), many toxicity tests still rely on animals (irritation, sensitization, acute toxicity, reproductive/developmental toxicity), even where other industrial sectors have already abandoned them. Bringing about change will require a paradigm shift in current approaches to testing - and a concerted effort to generate better data on risks to human health from exposure to leachable chemicals from medical devices, and to boost confidence...
In Vitro Cellular Developmental Biology Journal of the Tissue Culture Association, May 1, 1992
Sodium butyrate (NaB), a 4-carbon fatty acid, has been reported to activate the metallothionein (... more Sodium butyrate (NaB), a 4-carbon fatty acid, has been reported to activate the metallothionein (MT) gene in certain carcinoma cell lines. Because the effects of NaB are dependent on the cell type investigated, this study was conducted to determine if NaB and its homologues induce MT in rat primary hepatocyte cultures. Hepatocytes were grown on monolayer for 12 h and subsequently treated with formate, acetate, propionate (NaP), NaB, and valeric acid for 10 to 58 h. To examine their interaction with known MT inducers, cadmium (Cd), zinc (Zn), or dexamethasone (Dex) were added to some cultures. MT protein in the cells was quantitated by the Cd-hemoglobin assay; MT-1 mRNA was analyzed by Northern blot hybridizations with oligonucleotide probes, and quantitated by slot-blot analysis. Among the 1 to 5 carbon carboxylic acids, only NaP (3 carbon) and NaB (4 carbon) induced MT. NaP and NaB alone produced a moderate increase in MT two- to fourfold over control), but when combined with Cd or Dex, an additive increase was observed. However, when combined with Zn, a synergistic increase was detected. NaB and Zn synergistically increased MT protein, but produced only an additive increase in MT mRNA, suggesting the involvement of some posttranscriptional event(s) in the NaB-Zn induction of MT. In conclusion, NaP and NaB induced MT in normal cultured rat hepatocytes, producing an additive increase in MT protein with Cd and Dex, and a synergistic increase in MT protein with Zn.
... of Phenolsulfonphthalein1 NASR H. ANAIZI2 and JULIUS J. COHEN Department of Physiology. ... 1... more ... of Phenolsulfonphthalein1 NASR H. ANAIZI2 and JULIUS J. COHEN Department of Physiology. ... 1978 ABSTRACT Anaizi, Nasr H. and Julius J. Cohen: The ef-fects of 2,3, 7,8-tetrach!orodibenzo-p-dioxin on the renal tubular secretion of phenolsulfon-phtha!ein. J. Pharmacol. ...
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2015
Carrageenan (CGN) is widely used in the food manufacturing industry as an additive that stabilize... more Carrageenan (CGN) is widely used in the food manufacturing industry as an additive that stabilizes and thickens food products. Standard animal safety studies in which CGN was administered in diet showed no adverse effects. However, several in vitro studies have reported that intestinal inflammation is caused by CGN and that this effect is mediated through Toll-Like-Receptor 4 (TLR4). The purpose of this study was to evaluate the ability of different types of CGN to bind and activate TLR4 signaling. To accomplish this a TLR4/MD-2/CD14/NFκB/SEAP reporter construct in a HEK293 cell line was used. The reporter molecule, secretable alkaline phosphatase (SEAP), was measured as an indicator of TLR4 activation. The test compounds were exposed to this system at concentrations of 0.1, 1, 10, 50, 100, 500, 1000, and 5000 ng/mL for 24 h. Cytotoxicity was evaluated following the 24 h exposure period by LDH leakage and ATP. CGN binding to serum proteins was characterized by Toluidine Blue. The re...
Toxicological sciences : an official journal of the Society of Toxicology, 2001
The cyclic siloxane octamethylcyclotetrasiloxane (D4) and the linear siloxane hexamethyldisiloxan... more The cyclic siloxane octamethylcyclotetrasiloxane (D4) and the linear siloxane hexamethyldisiloxane (HMDS) have numerous industrial and consumer applications and thus have the potential for human exposure. The present study was undertaken to examine potential estrogenic and antiestrogenic activities of D4 and HMDS. To address potential differences in sensitivity between rat strains the study used both Sprague-Dawley (SD) and Fischer 344 (F-344) rats. Estrogenicity of the test compounds was determined by measuring absolute and relative uterine weights in immature rats and by monitoring uterine epithelial cell height. In order to place the data obtained for D4 into perspective relative to strong and weak estrogenic compounds, the response produced by D4 at 0, 10, 50, 100, 250, 500, and 1000 mg/kg/day was compared to responses produced by ethinyl estradiol (EE) (1, 3, 10, or 30 microg/kg/day), diethylstilbestrol dipropionate (DES-DP) (0.5, 1.5, 5, 15 microg/kg/day), and coumestrol (CE) ...
Distribution of Cd to various organs following iv administration of CdCl2 (3.5 mg Cd/kg) resulted... more Distribution of Cd to various organs following iv administration of CdCl2 (3.5 mg Cd/kg) resulted in more than 43% of total tissue Cd accumulating in the liver. In contrast, after CdMT administration (0.5 mg Cd/kg), only 1% of the Cd was found in liver. Rats administered CdCl2 (1.0 mg Cd/kg) had hepatic MT values 30-fold greater than controls and a hepatic Cd concentration of 17 micrograms/g. In comparison, rats treated with CdMT (0.4 mg Cd/kg) had hepatic MT concentrations 7-fold greater than controls and a hepatic Cd concentration of 0.80 micrograms/g. However, when hepatic MT levels were normalized to tissue Cd concentrations, induction of MT by CdMT was 5-fold greater than by CdCl2. Northern and slot-blot analyses of mRNA showed that both CdCl2 and CdMT coordinately increased MT mRNA. These data suggest that both CdMT and CdCl2 increase hepatic MT by similar mechanisms. A dose-response increase in MT produced by CdCl2 indicated a biphasic response, with low doses producing relat...
Since March 2013, animal use for cosmetics testing for the European market has been banned. This ... more Since March 2013, animal use for cosmetics testing for the European market has been banned. This requires a renewed view on risk assessment in this field. However, in other fields as well, traditional animal experimentation does not always satisfy requirements in safety testing, as the need for human-relevant information is ever increasing. A general strategy for animal-free test approaches was outlined by the US National Research Council`s vision document for Toxicity Testing in the 21st Century in 2007. It is now possible to provide a more defined roadmap on how to implement this vision for the four principal areas of systemic toxicity evaluation: repeat dose organ toxicity, carcinogenicity, reproductive toxicity and allergy induction (skin sensitization), as well as for the evaluation of toxicant metabolism (toxicokinetics) (Fig. 1). CAAT-Europe assembled experts from Europe, America and Asia to design a scientific roadmap for future risk assessment approaches and the outcome was...
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Papers by James Mckim