Is It Adverse, Nonadverse, Adaptive, or Artifact?

Pandiri, Arun R.; Kerlin, Roy L.; Mann, Peter C.; Everds, Nancy E.; Sharma, Alok; Myers, L. Peyton; Steinbach, Thomas

doi:10.1177/0192623316672352

Cited by 30 publications

(28 citation statements)

References 22 publications

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“…However, these findings lacks relevance for humans because of differences in anatomical structures 32 . Even though squamous metaplasia is an adaptive or protective change, it should be considered an adverse effect because of the severity of the lesion and concomitant degenerative/necrotic and/or hyperplastic changes 33 . Interestingly, the grade of squamous metaplasia of lung in our study is found to be more severe than that in 13-week inhalation study of PHMG•HCl(Inhalation concentration: 0 mg/m 3 , 0.13 mg/m 3 , 0.4 mg/m 3 , and 1.20 mg/m 3 ) 30 .…”

Section: Discussionmentioning

confidence: 99%

Toxicity of humidifier disinfectant polyhexamethylene guanidine hydrochloride by two-week whole body-inhalation exposure in rats

Lee

Seo

2020

J Toxicol Pathol

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The use of polyhexamethylene guanidine hydrochloride (PHMG•HCl) as a humidifier disinfectant caused an outbreak of pulmonary disease, leading to the deaths of pregnant women and children in South Korea. However, limited information is available on the inhalation toxicity of PHMG•HCl. Therefore, this study aimed to characterize the subacute inhalation toxicity of PHMG•HCl by whole-body exposure in rats. F344 rats were exposed to 0 mg/m 3 , 1 mg/m 3 , 5 mg/m 3 , or 25 mg/m 3 of PHMG•HCl for 6 h/day, 5 days/week for two weeks via whole-body inhalation. Emaciation and rale were observed in rats in the 25 mg/m 3 PHMG•HCl group. Significant changes in body weight, hematology, serum chemistry and organ weight were observed in all PHMG•HCl-exposed groups. Gross lesions showed ballooning or red focus in the lungs of rats in the PHMG•HCl-exposed groups. In histopathological examination, most of histological lesions (including degeneration, atrophy, ulcer, inflammatory cell infiltration, inflammation, and fibrosis in nasal cavity, larynx, trachea, and lungs) indicated tissue damage by PHMG•HCl in all PHMG•HCl-exposed groups. Additionally, atrophy of the spleen, thymus, and reproductive organs; immaturity of the testes; and cell debris in the epididymides were affected by the reduction in body weight in PHMG•HCl-exposed groups. In conclusion, two-week repeated whole-body inhalation exposure of rats to PHMG•HCl reveled toxic effects on the respiratory system and secondary effects on other organs. The results of this study indicate that the no observable adverse effect level (NOAEL) for PHMG•HCl is below 1 mg/m 3 .

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Section: Discussionmentioning

confidence: 99%

Toxicity of humidifier disinfectant polyhexamethylene guanidine hydrochloride by two-week whole body-inhalation exposure in rats

Lee

Seo

2020

J Toxicol Pathol

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“…Mitochondrial toxicities, such as cardiomyopathy, hepatic steatosis, pancreatitis, skeletal myopathy, lactic acidosis and neuropathy (33), have been associated with certain nucleoside analogs. In vivo , the extent of systemic re-distribution of 2′-F-purines appears to be minimal following generation from GalNAc–siRNAs in liver and kidney and, to date, there is no evidence of liver failure or nephropathy in clinical (33) or pre-clinical (34) studies with STC or ESC GalNAc–siRNAs. At completion of the 2-year rat carcinogenicity study where rats were dosed weekly with up to 100 mg/kg of two STC GalNAc–siRNA conjugates containing 22 2′-F-ribonucleotides, treatment-related ultrastructural changes involving mitochondria observed in liver hepatocytes and skeletal myocytes (soleus muscle) were limited to elongated and ring-shaped/cup-shaped mitochondrial profiles and enlarged mitochondria in animals given either ≥10 mg/kg of revusiran or 30 mg/kg of siTTR-3.…”

Section: Discussionmentioning

confidence: 99%

“…Of these two ultrastructural findings, enlargement of mitochondria was the only finding not seen in some control animals, whereas elongated mitochondria were occasionally observed in the hepatocytes of control animals, which suggested the incidence of these findings was not solely related to chronic administration of revusiran or siTTR-3. Thus, utilizing ‘a weight of evidence approach’, the ultrastructural mitochondrial changes that were observed in affected hepatocytes and myocytes (i.e., the elongation and enlargement) were not associated with plasma lactate elevations, or with adverse changes such as mitophagy, mitochondrial degeneration/necrosis or alterations in cristae morphology (34).…”

Section: Discussionmentioning

confidence: 99%

Safety evaluation of 2′-deoxy-2′-fluoro nucleotides in GalNAc-siRNA conjugates

Janas

Zlatev

Liu

et al. 2019

Nucleic Acids Research

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For oligonucleotide therapeutics, chemical modifications of the sugar-phosphate backbone are frequently used to confer drug-like properties. Because 2′-deoxy-2′-fluoro (2′-F) nucleotides are not known to occur naturally, their safety profile was assessed when used in revusiran and ALN-TTRSC02, two short interfering RNAs (siRNAs), of the same sequence but different chemical modification pattern and metabolic stability, conjugated to an N -acetylgalactosamine (GalNAc) ligand for targeted delivery to hepatocytes. Exposure to 2′-F-monomer metabolites was low and transient in rats and humans. In vitro , 2′-F-nucleoside 5′-triphosphates were neither inhibitors nor preferred substrates for human polymerases, and no obligate or non-obligate chain termination was observed. Modest effects on cell viability and mitochondrial DNA were observed in vitro in a subset of cell types at high concentrations of 2′-F-nucleosides, typically not attained in vivo . No apparent functional impact on mitochondria and no significant accumulation of 2′-F-monomers were observed after weekly administration of two GalNAc–siRNA conjugates in rats for ∼2 years. Taken together, the results support the conclusion that 2′-F nucleotides can be safely applied for the design of metabolically stabilized therapeutic GalNAc–siRNAs with favorable potency and prolonged duration of activity allowing for low dose and infrequent dosing.

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“…However, in several cases and based on experts’ judgment, a dose might be considered as creating adversity due to the disturbance of a set of endpoints which in isolation cannot be considered as adverse or due to their nature or due to the size of disturbance [32,33]. Further effort is needed to reach consensus among regulatory toxicologists regarding in which level each effect should be consider adverse [[34], [35], [36], [37]]. This long-avoided discussion is now necessary also in order to set the critical effect sizes for the benchmark dose [38].…”

Section: Discussionmentioning

confidence: 99%

Proposing new approaches for the risk characterisation of single chemicals and chemical mixtures: The source related Hazard Quotient (HQS) and Hazard Index (HIS) and the adversity specific Hazard Index (HIA)

Γούμενου

Tsatsakis

2019

Toxicology Reports

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A hazard quotient (HQ) for a single chemical and the hazard index (HI) for a mixture of chemicals were first described as approaches for risk characterisation by the EPA. HQ is defined as the ratio of exposure to an appropriate reference dose such as the ADI. HI is the sum of the HQs of the chemicals in a mixture. HQ and HI have been used to characterise risk after various exposure scenarios. However, both approaches have a significant limitation in the way they are used. The accurate use of HQ or HI requires estimation of aggregate exposure, that is, exposure to a given chemical(s) from all possible relevant sources. In many studies, risk is assessed assuming exposure from a specific source such as, consumption of water or a specific food item, in which chemical(s) concentration(s) have been measured. In this case the classic HQ/HI approach can result in significant underestimation of risk. For this purpose, we developed an alternative approach, named as Source Related HQ (HQs) where HQ S is the ratio of the exposure from the specific source of interest to the respected reference values. According to our approach the HQ S , before being compared to the reference dose, should be adjusted by a correction factor, in order to simulate aggregated exposure. A correction factor can be calculated based on the permitted exposure contribution from the specific source to the permitted aggregated exposure. Another important limitation specific to the HI approach is the use of chemical specific ADIs that do not correspond to the same critical effect. In this study, we present an analysis based on the individual critical effects, in order to derive the critical effect and an adversity specific Hazard Index (HI A ) and risk characterisation for the whole mixture.

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Is It Adverse, Nonadverse, Adaptive, or Artifact?

Cited by 30 publications

References 22 publications

Toxicity of humidifier disinfectant polyhexamethylene guanidine hydrochloride by two-week whole body-inhalation exposure in rats

Toxicity of humidifier disinfectant polyhexamethylene guanidine hydrochloride by two-week whole body-inhalation exposure in rats

Safety evaluation of 2′-deoxy-2′-fluoro nucleotides in GalNAc-siRNA conjugates

Proposing new approaches for the risk characterisation of single chemicals and chemical mixtures: The source related Hazard Quotient (HQS) and Hazard Index (HIS) and the adversity specific Hazard Index (HIA)

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