Development of an inhalation unit risk factor for ethylene dibromide

Abstract

The Texas Commission on Environmental Quality (TCEQ) follows standard scientific methods to develop up-to-date toxicity factors for chemicals emitted in the state of Texas. An inhalation unit risk factor (URF) was developed for ethylene dibromide (EDB, CAS 106-93-4) based on an increased incidence of nasal cavity adenocarcinomas observed in female rats in a 2-year inhalation cancer bioassay conducted by the National Toxicology Program (NTP). The NTP study provided evidence of several EDB-induced tumors in male and female rats and in female mice. Tumor incidences that were statistically increased at the low dose and that showed a statistically significant increasing trend were considered in identifying the critical effect. Following benchmark concentration (BMC) modeling and animal-to-human dosimetric adjustments, the increased incidence of nasal cavity adenocarcinomas observed in female rats was determined to be the most sensitive tumorigenic effect in the most sensitive species and sex and was utilized as the carcinogenic endpoint for the development of the URF. The 95% lower confidence limit of the BMC at the 10% excess risk level (BMCL₁₀ of 292.8 ppb) was determined for calculation of the URF. The resulting URF based on increased nasal cavity adenocarcinomas observed in female rats is 3.4E-04 per ppb (4.4E-05 per µg/m³). The lifetime air concentration corresponding to a no significant excess risk level of one in 100,000 is 0.029 ppb (0.22 µg/m³), which is considered sufficiently health-protective for use in protecting the general public against the potential carcinogenic effects of chronic exposure to EDB in ambient air.

Keywords:

• Ethylene dibromide
• 1,2-dibromoethane
• unit risk factor
• cancer
• inhalation

Introduction

Ethylene dibromide (EDB) is a heavy brominated hydrocarbon, which is manufactured by reacting ethylene and bromine (Ott et al., 1980). EDB is mainly a synthetic chemical; however, it is also formed naturally by microalgae growth found in small amounts in the ocean (USEPA, 2004). Until 1978, EDB was primarily used as a lead scavenger in antiknock mixtures added to gasoline. EDB was also used as a pesticide, a chemical intermediate for the production of resins, gums, waxes and dyes, in pharmaceuticals and has also been used as a flame retardant. In the 1970 s and early 1980 s, EDB was sprayed directly onto fruits, vegetables and grain crops to control insects. In 1984, the United States Environmental Protection Agency (USEPA) eliminated most uses of EDB in the US (ATSDR, 1992).

EDB is released into the environment from manufacturing use and emissions at waste sites. It is persistent in the environment, especially in groundwater and breaks down slowly in air (over 4–5 months) and surface water (2 months) (ATSDR, 1992). According to USEPA’s Toxics Release Inventory (TRI), total air emissions of EDB in the US and Texas have declined since 1988. Total air emissions in the US were approximately 63,000 pounds in 1988 and declined to approximately 836 pounds in 2015. In 1988, total air emissions of EDB in Texas were 2900 pounds compared to 15 pounds in 2015 (USEPA, 2015). Similar to the TRI, the Texas Commission on Environmental Quality’s (TCEQ) Point Source Emissions Inventory (EI) Program conducts an annual survey of refineries and other industrial sites that meet the reporting criteria in the TCEQ emissions inventory rule (30 Texas Administrative Code §101.10). Although the TRI and EI programs are similar in nature, the emissions reporting criteria differs. Facilities that manufacture or process over 25,000 pounds a year of a specific chemical are required to report emissions to the TRI (USEPA, 2016). The EI rule states that any facility that emits or has the potential to emit 10 tons per year of any single hazardous air pollutants (HAP) as defined in Federal Clean Air Act is required to submit emissions inventories (TAC, 2016). EDB is a HAP that is often a byproduct from sulfur conversion plants that use a process to remove sulfur from feed streams. Therefore, although some Texas facilities are not manufacturing EDB, emissions are still possible from other processes. Thus, certain facilities are required to report to the TCEQ EI but not the USEPA TRI. In 2015, according to the TCEQ’s EI, EDB emissions were estimated at 3300 lbs. EDB is monitored for by the TCEQ’s ambient air monitoring program and results are reviewed on a monthly and annual basis. Since 2000, 99.99% of all validated 24h canister measurements have been below the method detection limit (MDL) of 0.50 parts per billion (ppb) (Texas Air Monitoring Information System, TAMIS 2015).

Methods

In order to estimate potential adverse health impacts associated with chemicals emitted in Texas, the TCEQ created state-of-the-science guidelines to develop toxicity factors (TCEQ, 2015) using the four-step risk assessment process formalized by the National Research Council (NRC, 1983, 1994) and procedures recommended in numerous USEPA risk assessment guidance documents and the scientific literature (USEPA, 1994, 2002; NRC, 2001). For carcinogenicity assessments, the TCEQ guidelines also use procedures recommended in the USEPA cancer guidelines (USEPA, 2005a,b). Consistent with the TCEQ and USEPA cancer guidelines, EDB is assumed to have a nonthreshold (e.g. linear) dose-response relationship in the low dose region as there are not sufficient mode of action data to adequately support using a threshold model. In this case, a linear extrapolation is performed to estimate excess lifetime risk at lower doses. The slope of the line from the point of departure (POD) to zero excess risk at zero exposure is the inhalation URF. In other words, the inhalation URF is the excess risk estimated to result from continuous lifetime exposure to an agent per ppb or µg/m³ in air. Further, as described in the 2005 USEPA cancer guidelines, in the absence of chemical-specific data indicating differential early-life sensitivity, the linear low-dose extrapolation approach provides adequate public health conservatism for children and sensitive populations (USEPA, 2005a,b).

Although human studies are preferred over animal studies in the derivation of an inhalation URF (TCEQ, 2015), no epidemiological studies suitable for derivation of a URF were available. Several studies have examined the correlation between excess cancer risk in humans and EDB exposure (summarized in USEPA, 2004 and ATSDR, 1992). However, these studies looked at industrial workers exposed to various chemicals including EDB and/or lack information on individual exposures, so causality cannot be determined based on human data. Therefore, a well-conducted animal study that used an adequate number of test animals and dose levels and examined appropriate tumorigenic endpoints was used (NTP, 1982).

Carcinogenicity assessment

The following sections describe the key data and steps used in the carcinogenicity assessment of EDB and the derivation of the inhalation URF. The TCEQ Guidelines outline the steps required to conduct a carcinogenicity assessment (Figures 1 and 2(a) of TCEQ, 2015) and include when animal data are used generally:

• Conduct a literature review and solicit information from interested parties.

• Perform carcinogenic weight of evidence (WOE) and mode of action (MOA) analyses (linear low-dose extrapolation is the default for a mutagenic or unknown MOA).

• Identify key studies with sufficient information to conduct dose-response analyses (human study data, although preferred, were not available for EDB).

• Conduct dose-response modeling with appropriate methods to derive a point of departure (e.g. POD from BMC modeling).

• Calculate the URF (e.g. 0.1/BMCL₁₀ = URF).

EDB has been evaluated for carcinogenic potential by the International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP) and the USEPA (Table 1). A request for relevant information from outside parties was posted on the TCEQ’s website and a literature search by the TCEQ was initially conducted in 2014. A detailed list of the databases and scientific literature sources commonly used by the TCEQ can be found in the TCEQ Guidelines (2015). Literature searches, WOE and MOA analyses are an integral part of the toxicity factor development process; however, these steps will not be discussed in full here as the purpose of this manuscript is to describe the process used to derive an inhalation URF for EDB. Although metabolites of EDB have shown to cause carcinogenic effects, no MOA studies have been conducted regarding tumorigenesis induced by the inhalation of EDB and therefore the default assumption is a nonthreshold (i.e. linear) dose-response at low doses. The USEPA (2005a) recognizes that there is rarely sufficient information about the MOA to scientifically justify the use of a threshold (i.e. nonlinear) dose-response model, which is the case for EDB. The default values used in the calculation of the inhalation URF are described in further detail where appropriate (dosimetric adjustment factors, duration adjustments) and are considered conservative, health-protective methods commonly used in regulatory dose-response assessments (TCEQ, 2015; USEPA, 1994, 2012a,b). The focus of this manuscript will be on the key study, dose-response modeling and URF derivation.

Table 1. Carcinogenic weight of evidence.

Group	Classification
IARC, 1999	Probably carcinogenic to humans
NTP, 2016	Reasonably anticipated to be a human carcinogen
USEPA, 2004	Likely to be carcinogenic to humans

Key study – NTP (1982)

NTP (1982) provided evidence of EDB-induced nasal cavity tumors and other benign and malignant tumors in male and female Fischer 344 rats and in female B6C3F1 mice in a 2-year inhalation cancer bioassay. They exposed 50 male and 50 female B6C3F1 mice at five weeks of age and 50 male and 50 female Fischer 344 rats at six weeks of age to EDB by whole-body inhalation at concentrations of 0, 10 and 40 ppm for 78–106 weeks (mice) and 88–106 weeks (rats) (50/sex/exposure group) for 6 h/day, 5 days/week. Untreated controls consisted of 50 rats and 50 mice of each sex exposed in chambers to charcoal and HEPA-filtered conditioned air. Mean body weights of high-dose rats and high-dose mice of both sexes were lower than untreated controls. Survival of high-dose rats (male and female) and of the low- and high-dose female mice were significantly lower than controls. Ascending, suppurative urinary tract infection that resulted in necrotic, ulcerative lesions was the principal cause of early death in control and dosed mice (unrelated to exposure of EDB).

Sacrifices were conducted at 106 weeks in control animals and at 104 weeks in low-dose animals. Survival in low-dose and control rats was similar for both sexes. Terminal sacrifices were conducted at 79 weeks in the male mice, 89 weeks in the high-dose male rats and 91 weeks in the high-dose female rats and mice. Although the treated male mice demonstrated histopathology similar to that seen in the female mice, high mortality in all groups that was not related to EDB exposure made these data unsuitable for quantitative assessment.

Rat study

Statistically significant incidences of carcinomas and adenocarcinomas of the nasal cavity were observed in low-(10 ppm) and high-dose (40 ppm) rats of both sex when compared to controls. Adenomatous polyps of the nasal cavity showed a statistically significant increase in low-dose male rats and the combined incidence of alveolar/bronchiolar adenomas and carcinomas were statistically significant in high-dose female rats. Hemangiosarcomas of the circulatory system and mesotheliomas of the tunica vaginalis were statistically increased in high-dose and both low- and high-dose male rats, respectively. Fibroadenomas of the mammary gland were significantly elevated in dosed female rats.

Mouse study

Alveolar/bronchiolar carcinoma and adenoma were significantly increased in high-dose mice of both sexes relative to controls. Hemangiosarcomas were significantly greater than controls in low- and high-dose female mice. High-dose female mice also had increased incidences of subcutaneous fibrosarcomas and nasal cavity carcinomas. Mammary gland adenocarcinomas were also significantly increased in low-dose females. These data are summarized in Table 2 (rat data) and Table 3 (mouse data).

Table 2. Statistically significant tumor incidences in rats exposed to EDB via inhalation (adapted from NTP, 1982).

Tumor type/Incidence	Control	10 ppm	40 ppm
Males
Nasal cavity carcinoma^a	0/50	0/50	21/50*
Nasal cavity adenoma	0/50	11/50*	0/50
Nasal cavity adenocarcinoma^a	0/50	20/50*	28/50*
Nasal cavity adenomatous polyp	0/50	18/50*	5/50*
Nasal cavity tumors^a^,^b	0/50	39/50*	41/50*
Hemangiosarcoma of circulatory system^a	0/50	1/50	15/50*
Pituitary adenoma	0/45	7/48*	2/47
Testis interstitial-cell tumor	35/50	45/50*	10/49*
Tunica vaginalis mesothelioma, NOS^a	0/50	7/50*	25/50*
Tunica vaginalis mesothelioma, NOS or malignant^a	1/50	8/50*	25/50*
Females
Nasal cavity carcinoma^a	0/50	0/50	25/50*
Nasal cavity adenoma	0/50	11/50*	3/50
Nasal cavity adenocarcinoma^a	0/50	20/50*	29/50*
Nasal cavity adenomatous polyp	0/50	5/50*	5/50*
Nasal cavity tumors^a^,^c	1/50	34/50*	43/50*
Lung alveolar/bronchiolar carcinoma or adenoma^a	0/50	0/48	5/47*
Hemangiosarcoma of circulatory system^a	0/50	0/50	5/50*
Pituitary adenoma	1/50	18/49*	4/45
Mammary gland fibroadenoma^a	4/50	29/50*	24/50*

Highlighted endpoints were further analyzed by the TCEQ for use as a POD.

NOS: not otherwise specified.

* Significant difference from control (p < .05), Fisher exact test.

^a Significant increasing trend (p < .05), Cochran-Armitage test.

^b Adenoma, carcinoma, adenocarcinoma, adenomatous polyp, papillary adenoma, squamous cell carcinoma or squamous cell papilloma.

^c Adenoma, carcinoma, adenocarcinoma, adenomatous polyp, papillary adenoma, papillary polyp or squamous cell carcinoma.

Table 3. Statistically significant tumor incidences in mice exposed to EDB via inhalation (adapted from NTP, 1982).

Tumor type/Incidence	Control	10 ppm	40 ppm
Males
Lung/Bronchus adenomatous polyp^a	0/41	0/48	5/46*
Lung alveolar/bronchiolar adenoma^a	0/41	0/48	11/46*
Lung alveolar/bronchiolar carcinoma^a	0/41	3/48	19/46*
Lung alveolar/bronchiolar adenoma or carcinoma^a	0/41	3/48	23/46*
Respiratory tumors^a^,^b	0/41	3/48	25/46*
Females
Nasal cavity carcinoma^a	0/50	0/50	6/50*
Nasal cavity carcinoma or adenoma^a	0/50	0/50	8/50*
Nasal cavity adenomatous polyp or adenoma^a	0/50	0/50	5/50*
Nasal cavity tumors^a^,^c	0/50	0/50	12/50*
Lung/bronchus adenoma^a	0/49	0/49	5/50*
Lung/bronchus adenoma or adenomatous polyp^a	0/49	0/49	6/50*
Lung alveolar/bronchiolar adenoma^a	3/49	7/49	13/50*
Lung alveolar/bronchiolar carcinoma^a	1/49	5/49	37/50*
Respiratory tumors^a^,^d	4/49	11/49*	42/50*
Hemangiosarcoma of circulatory system^a	0/50	11/50*	23/50*
Subcutaneous tissue or rib fibrosarcoma^a	0/50	5/50*	11/50*
Hematopoietic system lymphoma and leukemia	8/50	7/50	1/50*
Pituitary adenoma	8/48	1/46*	0/40*
Mammary gland adenocarcinoma	2/50	14/50*	8/50*

Highlighted endpoints were further analyzed by the TCEQ for use as a POD.

* Significant difference from control (p < .05), Fisher exact test.

^a Significant increasing trend (p < .05), Cochran-Armitage test.

^b Adenoma, adenomatous polyp, alveolar/bronchiolar adenoma or alveolar/bronchiolar carcinoma.

^c Adenoma, carcinoma, adenomatous polyp or hemangiosarcoma.

^d Adenoma, carcinoma, adenomatous polyp, alveolar/bronchiolar adenoma or alveolar/bronchiolar carcinoma.

Benchmark concentration (BMC) modeling

The NTP (1982) study clearly demonstrated statistically significant tumor incidences with increasing exposure levels at several sites in multiple species. Since several tumor types in both rats and mice were observed, the tumor incidences that were statistically increased at the low dose (10 ppm) compared to control and that showed a statistically significant increasing trend (i.e. more sensitive endpoints with statistical increases beginning at the lowest dose and a better defined dose-response) were considered in identifying the critical effect (Tables 2 and 3).

To this end, the TCEQ performed BMC modeling using USEPA BMD software (version 2.6) for the highlighted data in Table 2 (rat data) and Table 3 (mouse data) which was taken from the NTP (1982) study. Data were used to predict 95% lower confidence limits on the BMCs using dichotomous models. A default benchmark response (BMR) of 10% was selected for extra risk (BMC₁₀) and BMCL₁₀. For the selected rat and mouse data, all of the available dichotomous and multistage cancer models were run and the best fit models (global goodness of fit p > .1, scaled residuals <|2|, lowest AIC/BMDL) are listed in Table 4. Modeling of the rat and mouse data from the NTP (1982) study resulted in several BMCL₁₀ values and since they are relatively close (within a factor of five), each of the identified tumorigenic endpoints were considered in the selection of the POD for the most sensitive endpoint (i.e. critical effect) following dosimetric adjustment to human equivalent concentrations (POD_HEC values).

Table 4. BMC Modeling for the neoplastic endpoints from NTP (1982).

Endpoint	Model	p value	AIC	BMC10	BMCL10
Male rats
Nasal cavity adenocarcinoma	Log logistic	.186	141.14	2.43	1.71
Nasal cavity tumors	No viable models	–	–	–	–
Tunica vaginalis mesothelioma, NOS or malignant	Quantal-linear	.849	127.12	6.37	4.74
Female rats
Nasal cavity adenocarcinoma	Log logistic	.267	139.89	2.32	1.64
Nasal cavity tumors	No viable models	–	–	–	–
Mammary gland fibroadenoma	No viable models	–	–	–	–
Female mice
Respiratory tumors	Probit	.888	127.88	7.46	6.02
Subcutaneous tissue or rib fibrosarcoma	Log logistic	.734	87.782	13.7	8.81
Circulatory system hemangiosarcoma	Multistage-cancer 2°	.432	125.26	5.98	4.55

Exposure duration adjustment

In the NTP (1982) study, animals were exposed for 6 hours/day, 5 days/week. An adjustment from a discontinuous to a continuous exposure duration was conducted (TCEQ, 2015) as follows: where:

D = Exposure duration, hours per day

F = Exposure frequency, days per week

The resulting POD_ADJ for each of the endpoints examined can be found in Table 5.

Table 5. Endpoints and POD_HEC for the neoplastic endpoints from NTP (1982).

Endpoint	POD/BMCL10 (ppm)	PODADJ (ppm)	Dosimstric adjustment	DAF	PODHEC (ppm)
Male Rats
Nasal cavity adenocarcinoma	1.71	0.3053	POE, ET	1	0.3053
Tunica vaginalis mesothelioma, NOS or malignant	4.74	0.8464	Systemic	1	0.8464
Female Rats
Nasal cavity adenocarcinoma	1.64	0.2928	POE, ET	1	0.2928
Female Mice
Respiratory tumors	6.02	1.075	POE, PU	3.21	19.32
Subcutaneous tissue or rib fibrosarcoma	8.81	1.5732	Systemic	1	1.5732
Circulatory system hemangiosarcoma	4.55	0.8125	Systemic	1	0.8125

Dosimetry adjustment from animal-to-human exposure

EDB is considered a Category 2 gas (EPA 2004). Since the critical adverse effects caused by EDB are both point of entry (POE) and systemic in nature, each endpoint will be treated as either a Category 1 (POE effects) or a Category 3 (systemic effects) gas (TCEQ, 2015). A dosimetry adjustment from an animal concentration to a human equivalent concentration (POD_HEC) for each of the identified endpoints was performed for EDB according to the subsections below.

POE effects – Category 1 gas

For Category 1 gases, the dosimetric adjustment factor (DAF) is dependent upon the site at which the POE effects occur. When the critical effect is in the extrathoracic (ET) respiratory tract region, which includes the nasal cavity, a DAF of one is applied based on information on animal-to-human inhalation gas dosimetric adjustments from recommendations in USEPA (2012a). Modeling demonstrates that in the absence of chemical-specific information to the contrary, internal dose equivalency in the ET region for rats (and other laboratory animals) and humans is approximately equivalent and uniformly distributed; therefore, adjustments by the ratio of minute volume (V_E) to surface area (SA) are not necessary (TCEQ, 2015). Thus, the POD_HEC for the endpoints in the ET region is equal to the POD_ADJ (Table 5).

When the critical effect is in the pulmonary (PU) region, as is observed in this case with respiratory tumors, the DAF is the ratio of the regional gas dose ratio of animal to human in the pulmonary region (RGDR_PU). This dosimetric adjustment is intended to capture the differences in distribution of gases to the pulmonary region in animals (in this case, mice), compared to humans. It has been found that this distributional difference can be captured in the ratio of the species minute volume and pulmonary surface area. where: V_E (ml/min) = minute volume

SA_PU = pulmonary surface area

A = animal

H = human

For respiratory tumors in female mice, the minute volume 0.041 L/min, was calculated using an average body weight of 35 grams and the standard mouse pulmonary surface area was 0.05 m² (USEPA, 1994). For humans, the standard minute volume was 13.8 L/min and pulmonary surface area was 54 m² (USEPA, 1994).

Systemic effects – Category 3 gas

For Category 3 gases, when available, animal and human blood:gas partition coefficients are used to dosimetrically adjust for species differences in toxicokinetics (TCEQ, 2015).

where: H_b/g = blood:gas partition coefficient

A = animal

H = human

Based on inhalation modeling and partition coefficient calculations provided for a number of chemicals in the USEPA (2012a) guidelines, the animal to human ratio is typically greater than one independent of the physical and chemical properties of the gas. Using a default of one is considered to be conservative in the absence of chemical specific data, meaning that it is predictive of higher risk to humans than is probably the case. Gargas et al. (1989) reported the rat H_b/g of 119 for EDB, which is greater than the estimated human H_b/g of 24.8. Thus, in this case, since the animal H_b/g is greater than the human H_b/g the default value of one was applied (USEPA, 2012a). Similarly, in order to be conservative, if H_b/g values are unknown, the default value for the H_b/g animal:human ratio is one (USEPA, 2012a). A blood:gas partition coefficient for EDB was not available for the mouse and in this case, a default value of one is also used (TCEQ, 2015). Therefore, the POD_HEC for each of the systemic endpoints is equal to the POD_ADJ (Table 5).

Determination of the critical tumorigenic effect and calculation of the URF

The lowest POD_HEC identified from the NTP (1982) study was 0.2928 ppm for nasal cavity adenocarcinomas in female rats (Table 5). This endpoint was selected as the critical tumorigenic effect and was used in the derivation of the URF. An almost identical POD_HEC (0.3053 ppm) was calculated for nasal cavity adenocarcinomas in male rats and two other endpoints were within a factor of three.

From this data, an inhalation URF can be derived using the following equation (TCEQ, 2015):

Discussion and conclusions

The inhalation URF presented here (3.4E-04 per ppb or 4.4E-05 per µg/m³) is based on the increased incidence of nasal cavity adenocarcinomas observed in female rats following chronic inhalation exposure to EDB (NTP, 1982). This URF represents the theoretical excess risk associated with lifetime exposure on a per unit air concentration basis (i.e. excess risk per µg/m³). For example, if one million people were exposed to a lifetime average concentration of 1 µg/m³ EDB, the potential upper bound theoretical excess risk would be 44 cancer cases, although actual risk could be as low as zero. The air concentration corresponding to a no significant excess risk level of one in 100,000 (TCEQ, 2015) is 0.029 ppb or 0.22 µg/m³, which will be used by the TCEQ as a comparison value for long-term average ambient air concentrations. The TCEQ considers the one in 100,000 no significant excess risk level air concentration (0.029 ppb or 0.22 µg/m³) to be sufficiently health-protective for use in protecting the general public against the potential carcinogenic effects of chronic exposure to EDB in ambient air (TCEQ, 2015). As this value will be used by the TCEQ for the evaluation of ambient air monitoring data in Texas, it is important to note that the method detection limit of 0.50 ppb currently used by the TCEQ is not sufficient to detect air concentrations at the one in 100,000 no significant excess risk level air concentration.

The USEPA (2004) derived a one in 100,000 excess risk level air concentration of 0.02 µg/m³ (0.0026 ppb) based on an inhalation URF of 6E-04 per µg/m³, which is an order of magnitude lower than the value derived by the TCEQ. The USEPA also used the NTP (1982) study to derive a critical effect, however, the critical endpoint chosen was the combined nasal tumors observed in male rats. The most significant difference in the development of these comparison values is the RGDR for the ET region. While the USEPA used an RGDR of 0.2 consistent with the USEPA (1994) reference concentration (RfC) methodology, the TCEQ used a value of one consistent with updated 2012 USEPA guidance, USEPA (2012b) details the use of a RGDR of one for gases that act in the ET region. Specifically, interspecies dosimetry modeling results indicate that for the ET region, the dose to animals can range from similar to up to sevenfold greater when compared to humans; therefore using the RGDR of one is considered to be conservative (USEPA, 2012a). The TCEQ updated its own guidance in accordance with this much more recent USEPA data and modeling (TCEQ, 2015). Although the combined incidence of nasal cavity tumors in male rats did not produce a viable model in the present study, the difference in dosimetric adjustment and the use of mortality adjusted data by the USEPA may explain the differences observed in the benchmark data and ultimately the URF.

Disclosure statement

No potential conflict of interest was reported by the authors.